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Tran GT, Bedi S, Rakesh P, Verma ND, Carter N, Robinson CM, Al-Atiyah R, Hall BM, Hodgkinson SJ. Autoantigen and IL-2 activated CD4 +CD25 +T regulatory cells are induced to express CD8 and are autoantigen specific in inhibiting experimental autoimmune encephalomyelitis. J Neuroimmunol 2025; 404:578611. [PMID: 40228404 DOI: 10.1016/j.jneuroim.2025.578611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/18/2025] [Accepted: 04/06/2025] [Indexed: 04/16/2025]
Abstract
Experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP) is a self-limiting disease model of multiple sclerosis. CD4+CD25+Foxp3+T cells play a role in limiting autoimmune disease but treatment with antigen naïve CD4+CD25+ cells does not reduce EAE. This study examined if in vitro activation by MBP and rIL-2 induced CD4+CD25+Foxp3+ cells that could inhibit EAE. Culture of CD4+CD8-CD25+cells from naïve rats with MBP and rIL-2 induced activated Treg that reduced the severity of clinical EAE and infiltration of CD8+T cells and macrophage into brain stem. CD4+CD25+T cells activated by an irrelevant autoantigen and rIL-2 did not suppress EAE. Resting CD4+CD25+T cells activated by autoantigen and rIL-2 have mRNA for Infgr, Il12rb2, Il5 but not Tbet, Gata3, Ilr5ra or Ifng. These changes in mRNA expression are the markers of Ts1 cells. A proportion of CD4+CD8-CD25+ cells activated by MBP/rIL-2 were induced to express CD8α, CD8β and CD62L. Depletion of CD4+CD8α+CD25+ cells removed the capacity of MBP and rIL-2 activated CD4+CD25+T cells to suppress EAE. This study demonstrated that in vitro activation of CD4+CD8-CD25+ cells by MBP/rIL-2 induced relevant antigen-specific Treg within days, which expressed CD8α, CD8β and CD62L with a Ts1 phenotype and that had greater potency than freshly isolated antigen naive CD4+CD25+Treg in suppressing clinical severity of EAE and immune inflammation in CNS. These findings may guide development of antigen-specific Treg for therapy.
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MESH Headings
- Animals
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Rats
- Autoantigens/immunology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/metabolism
- Interleukin-2/pharmacology
- Interleukin-2/immunology
- Myelin Basic Protein/immunology
- Rats, Inbred Lew
- Female
- Interleukin-2 Receptor alpha Subunit/metabolism
- CD8 Antigens/biosynthesis
- CD8 Antigens/metabolism
- Cells, Cultured
- Lymphocyte Activation/drug effects
- Lymphocyte Activation/immunology
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Affiliation(s)
- Giang T Tran
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia.
| | - Sukhandep Bedi
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia
| | - Prateek Rakesh
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia.
| | - Nirupama D Verma
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia.
| | - Nicole Carter
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Departments of Neurology Liverpool Health Service, Liverpool, NSW, Australia; Department of Nephrology, Liverpool Health Service, Liverpool, NSW, Australia
| | - Catherine M Robinson
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Departments of Neurology Liverpool Health Service, Liverpool, NSW, Australia; Department of Nephrology, Liverpool Health Service, Liverpool, NSW, Australia
| | - Ranje Al-Atiyah
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Departments of Neurology Liverpool Health Service, Liverpool, NSW, Australia; Department of Nephrology, Liverpool Health Service, Liverpool, NSW, Australia
| | - Bruce M Hall
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Department of Nephrology, Liverpool Health Service, Liverpool, NSW, Australia.
| | - Suzanne J Hodgkinson
- Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Departments of Neurology Liverpool Health Service, Liverpool, NSW, Australia.
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Sufianov A, Agaverdiev M, Mashkin A, Ilyasova T. The functions of immune system-derived miRNAs in cardiovascular diseases. Noncoding RNA Res 2025; 11:91-103. [PMID: 39736852 PMCID: PMC11683256 DOI: 10.1016/j.ncrna.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/02/2024] [Accepted: 11/13/2024] [Indexed: 01/01/2025] Open
Abstract
Cardiovascular diseases (CVD) are the foremost cause of mortality worldwide, with recent advances in immunology underscoring the critical roles of immune cells in their onset and progression. MicroRNAs (miRNAs), particularly those derived from the immune system, have emerged as vital regulators of cellular functions within the cardiovascular landscape. This review focuses on "immuno-miRs," a class of miRNAs that are highly expressed in immune cells, including T cells, B cells, NK cells, neutrophils, and monocytes/macrophages, and their significant role in controlling immune signaling pathways. Highlighting recent studies in human and animal models, this review examines how miRNAs influence both innate and adaptive immune responses and explores their potential as therapeutic targets for CVD. Special emphasis is placed on miRNAs that regulate T cells, suggesting that targeted manipulation of these miRNA pathways could offer new strategies for CVD treatment. As research in cardiovascular immunology advances, this review aims to provide a thorough overview of the potential of immune system-derived miRNAs to revolutionize CVD management and therapy, addressing a major global health challenge.
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Affiliation(s)
- Albert Sufianov
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Murad Agaverdiev
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
| | - Andrey Mashkin
- Educational and Scientific Institute of Neurosurgery, Рeoples’ Friendship University of Russia (RUDN University), Moscow, Russia
- Department of Neurosurgery, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Tatiana Ilyasova
- Bashkir State Medical University, Ufa, Republic of Bashkortostan, 3 Lenin Street, 450008, Russia
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Liu H, Dai H, Qiu F, Chen Y, Liang CL, Yang B, Gong N, Bromberg JS, Dai Z. Electrostimulation suppresses allograft rejection via promoting lymphatic regulatory T cell migration mediated by lymphotoxin - lymphotoxin receptor β signaling. Am J Transplant 2024; 24:2187-2198. [PMID: 38992495 DOI: 10.1016/j.ajt.2024.06.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/13/2024]
Abstract
Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin β receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.
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Affiliation(s)
- Huazhen Liu
- Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Traditional Chinese Medicine Syndrome, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Helong Dai
- Department of Kidney Transplantation, Center of Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, China
| | - Feifei Qiu
- Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuchao Chen
- Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Chun-Ling Liang
- Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Bin Yang
- Department of Cardiovascular Sciences, College of Life Sciences University of Leicester, Leicester, UK
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation of Ministry of Education, National Health Commission and Chinese Academy of Medical Sciences, Wuhan, Hubei, China.
| | - Jonathan S Bromberg
- Kidney and Pancreas Transplantation, Department of Surgery and Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
| | - Zhenhua Dai
- Section of Immunology, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
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Zhu J, Yang L, Xia J, Zhou N, Zhu J, Zhu H, Chen J, Qing K, Duan CW. Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease. Transplantation 2024; 108:e404-e416. [PMID: 38773837 DOI: 10.1097/tp.0000000000005069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2024]
Abstract
BACKGROUND Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. METHODS In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. RESULTS In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. CONCLUSIONS Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.
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Affiliation(s)
- Jianmin Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liting Yang
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xia
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Neng Zhou
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayao Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Zhu
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Chen
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Qing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cai-Wen Duan
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Chen T, Li J, Wei X, Yao H, Zhu L, Liu J, Liu Y, Wang P, Feng Y, Gao S, Liu H, Wang L, Zhao L, Gao L, Zhang C, Gao L, Zhang X, Kong P. Efficiency and Toxicity of Imatinib Mesylate Combined with Atorvastatin Calcium in the Treatment of Steroid-Refractory Chronic Graft-versus-Host Disease: A Single-Center, Prospective, Single-Arm, Open-Label Study. Acta Haematol 2024; 147:499-510. [PMID: 38232716 DOI: 10.1159/000536174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 12/26/2023] [Indexed: 01/19/2024]
Abstract
INTRODUCTION Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported that imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. METHODS Sixty SR-cGVHD patients were entered into this trial to investigate the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets, and adverse events. RESULTS At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes, and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, p < 0.0001). The overall survival in patients with ORR was improved (p = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (p = 0.021, HR = 0.335, 95% CI: 0.133-0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (p = 0.0117) and Th17 cells (p = 0.0171) decreased, while the number of Treg cells (p = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia, which were 13.3%, 11.7%, and 11.7%, respectively. CONCLUSION Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process.
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Affiliation(s)
- Ting Chen
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - JiaLi Li
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Xiao Wei
- Department of Endocrinology, The General Hospital of Western Theater Command PLA, Sichuan, China
| | - Han Yao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - LiDan Zhu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Jia Liu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - YuQing Liu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Ping Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - YiMei Feng
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - ShiChun Gao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - HuanFeng Liu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Lu Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Lu Zhao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Cheng Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Lei Gao
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
| | - PeiYan Kong
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing, China
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Ren D, Chen J, Yu M, Yi C, Hu X, Deng J, Guo S. Emerging strategies for tissue engineering in vascularized composite allotransplantation: A review. J Tissue Eng 2024; 15:20417314241254508. [PMID: 38826796 PMCID: PMC11143860 DOI: 10.1177/20417314241254508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 04/28/2024] [Indexed: 06/04/2024] Open
Abstract
Vascularized composite allotransplantation (VCA), which can effectively improve quality of life, is a promising therapy for repair and reconstruction after face or body trauma. However, intractable issues are associated with VCA, such as the inevitable multiple immunogenicities of different tissues that cause severe rejection, the limited protocols available for clinical application, and the shortage of donor sources. The existing regimens used to extend the survival of patients receiving VCAs and suppress rejection are generally the lifelong application of immunosuppressive drugs, which have side effects. Consequently, studies aiming at tissue engineering methods for VCA have become a topic. In this review, we summarize the emerging therapeutic strategies for tissue engineering aimed to prolong the survival time of VCA grafts, delay the rejection and promote prevascularization and tissue regeneration to provide new ideas for future research on VCA treatment.
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Affiliation(s)
- Danyang Ren
- Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jun Chen
- Department of Plastic Surgery, Linhai Branch, The Second Affiliated Hospital, Zhejiang University School of Medicine, Taizhou, Zhejiang, China
| | - Meirong Yu
- Center for Basic and Translational Research, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chenggang Yi
- Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xueqing Hu
- Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Junjie Deng
- Joint Centre of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Joint Centre of Translational Medicine, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
- Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, China
| | - Songxue Guo
- Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou, Zhejiang, China
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Baron KJ, Turnquist HR. Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy. Organogenesis 2023; 19:2164159. [PMID: 36681905 PMCID: PMC9870008 DOI: 10.1080/15476278.2022.2164159] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded ex vivo and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.
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Affiliation(s)
- Kassandra J. Baron
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Infectious Disease and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA,CONTACT Hēth R. Turnquist Departments of Surgery, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute 200 Lothrop Street, BST W1542, PittsburghPA 15213, USA
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Guinan EC, Contreras-Ruiz L, Crisalli K, Rickert C, Rosales I, Makar R, Colvin R, Geissler EK, Sawitzki B, Harden P, Tang Q, Blancho G, Turka LA, Markmann JF. Donor antigen-specific regulatory T cell administration to recipients of live donor kidneys: A ONE Study consortium pilot trial. Am J Transplant 2023; 23:1872-1881. [PMID: 37422112 DOI: 10.1016/j.ajt.2023.06.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 05/26/2023] [Accepted: 06/20/2023] [Indexed: 07/10/2023]
Abstract
Regulatory T cells (Tregs) can inhibit cellular immunity in diverse experimental models and have entered early phase clinical trials in autoimmunity and transplantation to assess safety and efficacy. As part of the ONE Study consortium, we conducted a phase I-II clinical trial in which purified donor antigen reactive (dar)-Tregs (CD4+CD25+CD127lo) were administered to 3 patients, 7 to 11 days after live donor renal transplant. Recipients received a modified immunosuppression regimen, without induction therapy, consisting of maintenance tacrolimus, mycophenolate mofetil, and steroids. Steroids were weaned off over 14 weeks. No rejection was seen on any protocol biopsy. Therefore, all patients discontinued mycophenolate mofetil 11 to 13 months posttransplant, per protocol. An early for-cause biopsy in 1 patient, 5 days after dar-Treg infusion, revealed absence of rejection and accumulation of Tregs in the kidney allograft. All patients had Treg-containing lymphoid aggregates evident on protocol biopsies performed 8 months posttransplant. The patients are now all >6 years posttransplant on tacrolimus monotherapy with excellent graft function. None experienced rejection episodes. No serious adverse events were attributable to Treg administration. These results support a favorable safety profile of dar-Tregs administered early after renal transplant, suggest early biopsy might be an instructive research endpoint and provide preliminary evidence of potential immunomodulatory activity.
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Affiliation(s)
- Eva C Guinan
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
| | - Laura Contreras-Ruiz
- Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
| | - Kerry Crisalli
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Charles Rickert
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Ivy Rosales
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Robert Makar
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Robert Colvin
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - Edward K Geissler
- University Hospital Regensburg, Department of Surgery, Regensburg, Germany.
| | - Birgit Sawitzki
- Institute of Medical Immunology, Virchow - Klinikum, Berlin, Germany.
| | - Paul Harden
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
| | - Qizhi Tang
- Division of Transplantation, Department of Surgery, University of California, San Francisco, California, USA.
| | - Giles Blancho
- Centre of Research in Transplantation and Immunology, Nantes University, Nantes, France.
| | - Laurence A Turka
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
| | - James F Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, Massachusetts, USA.
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Sun J, Wang T, Bian J, Shi W, Ruan Q. Immune tolerance induced in the anterior chamber ameliorates corneal transplant rejection. Clin Immunol 2023; 257:109797. [PMID: 37776968 DOI: 10.1016/j.clim.2023.109797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/26/2023] [Indexed: 10/02/2023]
Abstract
The relevance of regulatory T cells (Tregs) in induction of tolerance against corneal allografts has been well established. However, whether Tregs can be induced in the anterior chamber and suppress local alloimmune response after corneal transplantation is largely unknown. In the current study we report that not only can alloantigen specific Tregs be generated in the anterior chamber during corneal transplantation, they also play important roles in suppressing allograft rejection. Allograft rejected mice exhibit reduced Treg induction in the anterior chamber and the ability of aqueous humor and corneal endothelial cells from allograft rejected mice to induce Tregs is compromised. Further analysis revealed that the expression of immune-tolerance-related molecules is significantly decreased. Finally, we demonstrate that increasing Treg cells specifically in the anterior chamber can effectively suppress allograft rejection and exhibits better efficacy in promoting corneal allograft survival than systemic administration of Treg cells. Our current study may provide new ideas for the prevention and treatment of corneal transplant rejection.
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Affiliation(s)
- Jijun Sun
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan 250021, China
| | - Ting Wang
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan 250021, China
| | - Jiang Bian
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao 266071, China
| | - Weiyun Shi
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan 250021, China; Eye Institute of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao 266071, China.
| | - Qingguo Ruan
- Eye Institute of Shandong First Medical University, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao 266071, China.
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10
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Inoue M, Tsuji Y, Ueno R, Miyamoto D, Tanaka K, Moriyasu Y, Shibata S, Okuda M, Ando D, Abe Y, Kamada H, Tsunoda SI. Bivalent structure of a TNFR2-selective and agonistic TNF-α mutein Fc-fusion protein enhances the expansion activity of regulatory T cells. Sci Rep 2023; 13:13762. [PMID: 37612373 PMCID: PMC10447426 DOI: 10.1038/s41598-023-40925-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 08/18/2023] [Indexed: 08/25/2023] Open
Abstract
Recently, TNF receptor type 2 (TNFR2) signaling was found to be involved in the proliferation and activation of regulatory T cells (Tregs), a subpopulation of lymphocytes that suppress immune responses. Tregs mediate peripheral immune tolerance, and the disruption of their functions causes autoimmune diseases or allergy. Therefore, cell expanders or regulators of Tregs that control immunosuppressive activity can be used to treat these diseases. We focused on TNFR2, which is preferentially expressed on Tregs, and created tumor necrosis factor-α (TNF-α) muteins that selectively activate TNFR2 signaling in mice and humans, termed R2agoTNF and R2-7, respectively. In this study, we attempted to optimize the structure of muteins to enhance their TNFR2 agonistic activity and stability in vivo by IgG-Fc fusion following single-chain homo-trimerization. The fusion protein, scR2agoTNF-Fc, enhanced the expansion of CD4+CD25+ Tregs and CD4+Foxp3+ Tregs and contributed to their immunosuppressive activity ex vivo and in vivo in mice. The prophylactic administration of scR2agoTNF-Fc suppressed inflammation in contact hypersensitivity and arthritis mouse models. Furthermore, scR2-7-Fc preferentially expanded Tregs in human peripheral blood mononuclear cells via TNFR2. These TNFR2 agonist-Fc fusion proteins, which have bivalent structures, are novel Treg expanders.
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Affiliation(s)
- Masaki Inoue
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
| | - Yuta Tsuji
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Reira Ueno
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Daisuke Miyamoto
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Keisuke Tanaka
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Yuka Moriyasu
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Saya Shibata
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Mei Okuda
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan
| | - Daisuke Ando
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
- National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Yasuhiro Abe
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
- National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan
| | - Haruhiko Kamada
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan
| | - Shin-Ichi Tsunoda
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan.
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
- Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
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11
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Chen Y, Chai H, Li Z, Liu B, Tan M, Li S, Ma Y. Gut microbiota and their metabolite profiles following peripheral nerve xenotransplantation. Heliyon 2023; 9:e18529. [PMID: 37554826 PMCID: PMC10404661 DOI: 10.1016/j.heliyon.2023.e18529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 07/08/2023] [Accepted: 07/20/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND Intestinal pathogens are associated with xenotransplantation tolerance and rejection. However, changes in the gut microbiota in patients who have undergone peripheral nerve xenotransplantation and their association with immune rejection have not yet been reported. OBJECTIVE We aimed to explore intestinal microbes and their metabolites at different time points after peripheral nerve transplantation to provide new insight into improving transplant tolerance. METHODS A peripheral nerve xenotransplantation model was constructed by suturing the segmented nerves of Sprague Dawley rats to those of C57 male mice using xenotransplantation nerve bridging. Fecal samples and intestinal contents were collected at three time points: before surgery (Pre group; n = 10), 1 month after transplantation (Pos1 m group; n = 10), and 3 months after transplantation (Pos3 m group; n = 10) for 16S DNA sequencing and nontargeted metabolome detection. RESULTS Alpha diversity results suggested that species diversity was significantly downregulated after peripheral nerve xenotransplantation. There were six gut flora genera with significantly different expression levels after xenotransplantation: four were downregulated and two were upregulated. A comparison of the Pre vs. Pos1 m groups and the Pos1 m vs. Pos3 m groups revealed that the most significant differentially expressed Kyoto Encyclopedia of Genes and Genomes metabolite pathways were involved in phenylalanine, tyrosine, and tryptophan biosynthesis, as well as histidine metabolism. Metabolites with a strong relationship to the differentially expressed microbial flora were identified. CONCLUSION Our study found lower gut microbiome diversity, with increased short-chain fatty acid (SCFA)-producing and sulfate-reducing bacteria at 1 month post peripheral nerve xenotransplantation, and these were decreased at 3 months post-transplantation. The identification of specific bacterial metabolites is essential for recognizing potential diagnostic markers of xenotransplantation rejection or characterizing therapeutic targets to prevent post-transplant infection.
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Affiliation(s)
- Yongsheng Chen
- Department of Neurosurgery, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, Guangdong, China
| | - Huihui Chai
- Department of Cerebrovascular Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510360, Guangdong, China
| | - Zhenzhen Li
- Department of Neurosurgery, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, Guangdong, China
| | - Bin Liu
- Department of Neurosurgery, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, Guangdong, China
| | - Minxuan Tan
- Department of Neurosurgery, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, Guangdong, China
| | - Shaopeng Li
- Department of Neurosurgery, Dongguan People's Hospital (Affiliated Dongguan Hospital, Southern Medical University), Dongguan, Guangdong, China
| | - Yanxia Ma
- Department of Neurosurgery, The National Key Clinical Specialty, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
- Department of Neurosurgery, The Engineering Technology Research Center of Education Ministry of China, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
- Department of Neurosurgery, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
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12
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Zhang QQ, Zhang WJ, Chang S. HDAC6 inhibition: a significant potential regulator and therapeutic option to translate into clinical practice in renal transplantation. Front Immunol 2023; 14:1168848. [PMID: 37545520 PMCID: PMC10401441 DOI: 10.3389/fimmu.2023.1168848] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 05/30/2023] [Indexed: 08/08/2023] Open
Abstract
Histone deacetylase 6 (HDAC6), an almost exclusively cytoplasmic enzyme, plays an essential role in many biological processes and exerts its deacetylation-dependent/independent effects on a variety of target molecules, which has contributed to the flourishing growth of relatively isoform-specific enzyme inhibitors. Renal transplantation (RT) is one of the alternatively preferred treatments and the most cost-effective treatment approaches for the great majority of patients with end-stage renal disease (ESRD). HDAC6 expression and activity have recently been shown to be increased in kidney disease in a number of studies. To date, a substantial amount of validated studies has identified HDAC6 as a pivotal modulator of innate and adaptive immunity, and HDAC6 inhibitors (HDAC6i) are being developed and investigated for use in arrays of immune-related diseases, making HDAC6i a promising therapeutic candidate for the management of a variety of renal diseases. Based on accumulating evidence, HDAC6i markedly open up new avenues for therapeutic intervention to protect against oxidative stress-induced damage, tip the balance in favor of the generation of tolerance-related immune cells, and attenuate fibrosis by inhibiting multiple activations of cell profibrotic signaling pathways. Taken together, we have a point of view that targeting HDAC6 may be a novel approach for the therapeutic strategy of RT-related complications, including consequences of ischemia-reperfusion injury, induction of immune tolerance in transplantation, equilibrium of rejection, and improvement of chronic renal graft interstitial fibrosis after transplantation in patients. Herein, we will elaborate on the unique function of HDAC6, which focuses on therapeutical mechanism of action related to immunological events with a general account of the tantalizing potential to the clinic.
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Affiliation(s)
- Qian-qian Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Wei-jie Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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13
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Ding X, Du Y, Sun B, Liu L, Le S, Wu C, Chen J, Chen X, Chen S, Xia J. MicroRNA let-7a mediates posttranscriptional inhibition of Nr4A1 and exacerbates cardiac allograft rejection. Cell Signal 2023:110783. [PMID: 37356602 DOI: 10.1016/j.cellsig.2023.110783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 05/23/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Acute allograft rejection remains a major obstacle after heart transplantation, and CD4+ T cells play a crucial role in allograft rejection. Upregulation of Nr4A1 could regulate CD4+ T-cell function and alleviate allograft rejection. However, the regulatory mechanism of Nr4A1 in allograft rejection remains elusive. METHODS BCLb/c mouse hearts were transplanted into WT C57BL/6 mice, and dynamic detection of the changes in Nr4A1 expression revealed that Nr4A1 was regulated posttranscriptionally after heart transplantation. Potential upstream miRNAs of Nr4A1 were screened, and the transfection of cells with these miRNA mimics/inhibitors and dual-luciferase reporter experiments were performed to clarify the regulatory mechanism of miRNAs on Nr4A1 expression. The miRNA agomiR/antagomiR was applied in vivo to validate the role of the corresponding miRNA in heart transplantation. Finally, Nr4A1 knockout mice and an adoptive T-cell cotransfer model were used to confirm the specific effects of miRNA. RESULTS The expression of Nr4A1 protein (rather than mRNA) exhibited a trend of initially increasing and then decreasing rapidly, and this phenomenon could not be reversed by lysosomal or proteasomal inhibitors. The miRNA let-7a directly binds to the Nr4A1 3'UTR and posttranscriptionally regulates Nr4A1 expression. The let-7a antagomiR prolonged allograft survival and regulated CD4+ T-cell function by upregulating Nr4A1 protein expression in CD4+ T cells. CONCLUSIONS This study confirmed that let-7a is a potential target for interfering with Nr4A1 expression in CD4+ T cells and preventing the pathological progression of cardiac allograft rejection.
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Affiliation(s)
- Xiangchao Ding
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yifan Du
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bing Sun
- Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Liang Liu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Sheng Le
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chuangyan Wu
- Departments of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiuling Chen
- Departments of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing Chen
- Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shanshan Chen
- Key Laboratory for Molecular Diagnosis of Hubei Province and Central Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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14
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Henschel P, Landwehr-Kenzel S, Engels N, Schienke A, Kremer J, Riet T, Redel N, Iordanidis K, Saetzler V, John K, Heider M, Hardtke-Wolenski M, Wedemeyer H, Jaeckel E, Noyan F. Supraphysiological FOXP3 expression in human CAR-Tregs results in improved stability, efficacy, and safety of CAR-Treg products for clinical application. J Autoimmun 2023; 138:103057. [PMID: 37224732 DOI: 10.1016/j.jaut.2023.103057] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/28/2023] [Accepted: 05/03/2023] [Indexed: 05/26/2023]
Abstract
The forkhead family transcription factor (FOXP3) is an essential regulator for the development of regulatory T cells (Tregs) and orchestrates both suppressive function and Treg lineage identity. Stable expression of FOXP3 enables Tregs to maintain immune homeostasis and prevent autoimmunity. However, under pro-inflammatory conditions, FOXP3 expression in Tregs can become unstable, leading to loss of suppressive function and conversion into pathogenic T effector cells. Therefore, the success of adoptive cell therapy with chimeric antigen receptor (CAR) Tregs is highly dependent on the stability of FOXP3 expression to ensure the safety of the cell product. To warrant the stable expression of FOXP3 in CAR-Treg products, we have developed an HLA-A2-specific CAR vector that co-expresses FOXP3. The transduction of isolated human Tregs with the FOXP3-CAR led to an increase in the safety and efficacy of the CAR-Treg product. In a hostile microenvironment, under pro-inflammatory and IL-2-deficient conditions, FOXP3-CAR-Tregs showed a stable expression of FOXP3 compared to Control-CAR-Tregs. Furthermore, additional exogenous expression of FOXP3 did not induce phenotypic alterations and dysfunctions such as cell exhaustion, loss of functional Treg characteristics or abnormal cytokine secretion. In a humanized mouse model, FOXP3-CAR-Tregs displayed an excellent ability to prevent allograft rejection. Furthermore, FOXP3-CAR-Tregs revealed coherent Treg niche-filling capabilities. Overexpression of FOXP3 in CAR-Tregs has thereby the potential to increase the efficacy and reliability of cellular products, promoting their clinical use in organ transplantation and autoimmune diseases.
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Affiliation(s)
- Pierre Henschel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Sybille Landwehr-Kenzel
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Niklas Engels
- Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Goettingen, Germany
| | - Andrea Schienke
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jakob Kremer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tobias Riet
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Department I of Internal Medicine, Tumor Genetics, University Hospital of Cologne and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Nella Redel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Konstantinos Iordanidis
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Valerie Saetzler
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katharina John
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Miriam Heider
- Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, Hannover, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Medical Microbiology, Essen University Hospital, University Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Liver Transplantation, Multi Organ Transplant Program, University Health Network, Toronto, University of Toronto, Canada
| | - Fatih Noyan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
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15
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Zhang W, Chen Y, Zhao Z, Zheng H, Wang S, Liao Z, Sheng T, Zhao S, Hou W, Yu X, He F, Yu J, Zhang Y, Gu Z. Adoptive T reg therapy with metabolic intervention via perforated microneedles ameliorates psoriasis syndrome. SCIENCE ADVANCES 2023; 9:eadg6007. [PMID: 37196084 PMCID: PMC11803960 DOI: 10.1126/sciadv.adg6007] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/14/2023] [Indexed: 05/19/2023]
Abstract
Regulatory T (Treg) cells underlie multiple autoimmune disorders and potentialize an anti-inflammation treatment with adoptive cell therapy. However, systemic delivery of cellular therapeutics often lacks tissue targeting and accumulation for localized autoimmune diseases. Besides, the instability and plasticity of Treg cells also induce phenotype transition and functional loss, impeding clinical translation. Here, we developed a perforated microneedle (PMN) with favorable mechanical performance and a spacious encapsulation cavity to support cell survival, as well as tunable channels to facilitate cell migration for local Treg therapy of psoriasis. In addition, the enzyme-degradable microneedle matrix could release fatty acid in the hyperinflammatory area of psoriasis, enhancing the Treg suppressive functions via the fatty acid oxidation (FAO)-mediated metabolic intervention. Treg cells administered through PMN substantially ameliorated psoriasis syndrome with the assistance of fatty acid-mediated metabolic intervention in a psoriasis mouse model. This tailorable PMN could offer a transformative platform for local cell therapy to treat a variety of diseases.
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Affiliation(s)
- Wentao Zhang
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yingxin Chen
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Institute of Advanced Magnetic Materials and International Research Center for EM Metamaterials, College of Materials and Environmental Engineering, Hangzhou Dianzi University, Hangzhou 310018, China
| | - Zhengjie Zhao
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hanqi Zheng
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Shenqiang Wang
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Ziyan Liao
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Tao Sheng
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Sheng Zhao
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wenhui Hou
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xinmin Yu
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Fang He
- Department of Burns and Wound Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jicheng Yu
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Yuqi Zhang
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of Burns and Wound Center, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
| | - Zhen Gu
- Key Laboratory for Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China
- Jinhua Institute of Zhejiang University, Jinhua 321299, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China
- National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
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16
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Ramos TL, Bolivar-Wagers S, Jin S, Thangavelu G, Simonetta F, Lin PY, Hirai T, Saha A, Koehn B, Su LL, Picton LK, Baker J, Lohmeyer JK, Riddle M, Eide C, Tolar J, Panoskaltsis-Mortari A, Wagner JE, Garcia KC, Negrin RS, Blazar BR. Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo. Blood 2023; 141:1337-1352. [PMID: 36564052 PMCID: PMC10082364 DOI: 10.1182/blood.2022018440] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/09/2022] [Accepted: 12/01/2022] [Indexed: 12/25/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex-disparate GVHD model of lethally irradiated BALB/c mice given T cell-depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ-transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.
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Affiliation(s)
- Teresa L. Ramos
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
| | - Sara Bolivar-Wagers
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Sujeong Jin
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Govindarajan Thangavelu
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Federico Simonetta
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
- Translational Research Center for Oncohematology, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Po-Yu Lin
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
| | - Toshihito Hirai
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
- Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Asim Saha
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Brent Koehn
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Leon L. Su
- Department of Molecular and Cellular Physiology, Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA
| | - Lora K. Picton
- Department of Molecular and Cellular Physiology, Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA
| | - Jeanette Baker
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
| | - Juliane K. Lohmeyer
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
| | - Megan Riddle
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Cindy Eide
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Jakub Tolar
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Angela Panoskaltsis-Mortari
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - John E. Wagner
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - K. Christopher Garcia
- Department of Molecular and Cellular Physiology, Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA
| | - Robert S. Negrin
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, CA
| | - Bruce R. Blazar
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics and the Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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Zhang K, Huang Q, Peng L, Lin S, Liu J, Zhang J, Li C, Zhai S, Xu Z, Wang S. The multifunctional roles of autophagy in the innate immune response: Implications for regulation of transplantation rejection. Front Cell Dev Biol 2022; 10:1007559. [PMID: 36619861 PMCID: PMC9810636 DOI: 10.3389/fcell.2022.1007559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/04/2022] [Indexed: 12/24/2022] Open
Abstract
Organ transplantation is the main treatment for end-stage organ failure, which has rescued tens of thousands of lives. Immune rejection is the main factor affecting the survival of transplanted organs. How to suppress immune rejection is an important goal of transplantation research. A graft first triggers innate immune responses, leading to graft inflammation, tissue injury and cell death, followed by adaptive immune activation. At present, the importance of innate immunity in graft rejection is poorly understood. Autophagy, an evolutionarily conserved intracellular degradation system, is proven to be involved in regulating innate immune response following graft transplants. Moreover, there is evidence indicating that autophagy can regulate graft dysfunction. Although the specific mechanism by which autophagy affects graft rejection remains unclear, autophagy is involved in innate immune signal transduction, inflammatory response, and various forms of cell death after organ transplantation. This review summarizes how autophagy regulates these processes and proposes potential targets for alleviating immune rejection.
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Affiliation(s)
- Kunli Zhang
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Qiuyan Huang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Laru Peng
- Guangzhou Laboratory, Guangzhou International BioIsland, Guangzhou, China
| | - Sen Lin
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Jie Liu
- Guangdong Yantang Dairy Co, Ltd, Guangzhou, China
| | - Jianfeng Zhang
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China,Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China
| | - Chunling Li
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Shaolun Zhai
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Zhihong Xu
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China,*Correspondence: Zhihong Xu, ; Sutian Wang,
| | - Sutian Wang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China,Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China,*Correspondence: Zhihong Xu, ; Sutian Wang,
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18
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Sanders JM, Jeyamogan S, Mathew JM, Leventhal JR. Foxp3+ regulatory T cell therapy for tolerance in autoimmunity and solid organ transplantation. Front Immunol 2022; 13:1055466. [PMID: 36466912 PMCID: PMC9714335 DOI: 10.3389/fimmu.2022.1055466] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/02/2022] [Indexed: 08/03/2023] Open
Abstract
Regulatory T cells (Tregs) are critical for tolerance in humans. The exact mechanisms by which the loss of peripheral tolerance leads to the development of autoimmunity and the specific role Tregs play in allograft tolerance are not fully understood; however, this population of T cells presents a unique opportunity in the development of targeted therapeutics. In this review, we discuss the potential roles of Foxp3+ Tregs in the development of tolerance in transplantation and autoimmunity, and the available data regarding their use as a treatment modality.
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Affiliation(s)
- Jes M. Sanders
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Shareni Jeyamogan
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - James M. Mathew
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Joseph R. Leventhal
- Department of Surgery, Comprehensive Transplant Center Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- Simpson Querrey Institute for BioNanotechnology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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19
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Tang Q, Leung J, Peng Y, Sanchez-Fueyo A, Lozano JJ, Lam A, Lee K, Greenland JR, Hellerstein M, Fitch M, Li KW, Esensten JH, Putnam AL, Lares A, Nguyen V, Liu W, Bridges ND, Odim J, Demetris AJ, Levitsky J, Taner T, Feng S. Selective decrease of donor-reactive T regs after liver transplantation limits T reg therapy for promoting allograft tolerance in humans. Sci Transl Med 2022; 14:eabo2628. [PMID: 36322627 PMCID: PMC11016119 DOI: 10.1126/scitranslmed.abo2628] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2024]
Abstract
Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.
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Affiliation(s)
- Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
| | - Joey Leung
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Yani Peng
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, School of Immunology and Microbial Sciences, King’s College London University, London WC2R 2LS, UK
| | - Juan-Jose Lozano
- Bioinformatic Platform, Biomedical Research Center in Hepatic and Digestive Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alice Lam
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Karim Lee
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - John R. Greenland
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Medical Service, San Francisco VA Health Care System, San Francisco, CA 94121, USA
| | - Marc Hellerstein
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Mark Fitch
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Kelvin W. Li
- Nutrition Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Jonathan H. Esensten
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA
- Department of Lab Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Amy L. Putnam
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Angela Lares
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Vinh Nguyen
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Weihong Liu
- Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Nancy D. Bridges
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA
| | - Jonah Odim
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA
| | - Anthony J. Demetris
- Thomas E. Starzl Transplantation Institute and Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Josh Levitsky
- Department of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Timucin Taner
- Departments of Surgery and Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Sandy Feng
- Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
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20
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Yan S, Kotschenreuther K, Deng S, Kofler DM. Regulatory T cells in rheumatoid arthritis: functions, development, regulation, and therapeutic potential. Cell Mol Life Sci 2022; 79:533. [PMID: 36173485 PMCID: PMC9522664 DOI: 10.1007/s00018-022-04563-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/31/2022] [Accepted: 09/17/2022] [Indexed: 11/06/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that mainly affects the joints but also leads to systemic inflammation. Auto-reactivity and dysregulation of self-tolerance are thought to play a vital role in disease onset. In the pathogenesis of autoimmune diseases, disturbed immunosuppressive properties of regulatory T cells contribute to the dysregulation of immune homeostasis. In RA patients, the functions of Treg cells and their frequency are reduced. Therefore, focusing on the re-establishment of self-tolerance by increasing Treg cell frequencies and preventing a loss of function is a promising strategy for the treatment of RA. This approach could be especially beneficial for those patients who do not respond well to current therapies. In this review, we summarize and discuss the current knowledge about the function, differentiation and regulation of Treg cells in RA patients and in animal models of autoimmune arthritis. In addition, we highlight the therapeutic potential as well as the challenges of Treg cell targeting treatment strategies.
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Affiliation(s)
- Shuaifeng Yan
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Konstantin Kotschenreuther
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany
| | - Shuya Deng
- Department of Ophthalmology, University of Cologne, Cologne, Germany
| | - David M Kofler
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpenerstr. 62, 50937, Cologne, Germany.
- Center for Integrated Oncology, Aachen Bonn Cologne Duesseldorf, Cologne, Germany.
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21
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Shao Y, Saaoud F, Cornwell W, Xu K, Kirchhoff A, Lu Y, Jiang X, Wang H, Rogers TJ, Yang X. Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity. Cells 2022; 11:2810. [PMID: 36139385 PMCID: PMC9497420 DOI: 10.3390/cells11182810] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 11/23/2022] Open
Abstract
CD4+ regulatory T cells (Tregs) respond to environmental cues to permit or suppress inflammation, and atherosclerosis weakens Treg suppression and promotes plasticity. However, the effects of smoking plus morphine (SM + M) on Treg plasticity remain unknown. To determine whether SM + M promotes Treg plasticity to T helper 17 (Th17) cells, we analyzed the RNA sequencing data from SM, M, and SM + M treated Tregs and performed knowledge-based and IPA analysis. We demonstrated that (1) SM + M, M, and SM upregulated the transcripts of cytokines, chemokines, and clusters of differentiation (CDs) and modulated the transcripts of kinases and phosphatases in Tregs; (2) SM + M, M, and SM upregulated the transcripts of immunometabolism genes, trained immunity genes, and histone modification enzymes; (3) SM + M increased the transcripts of Th17 transcription factor (TF) RORC and Tfh factor CXCR5 in Tregs; M increased the transcripts of T helper cell 1 (Th1) TF RUNX3 and Th1-Th9 receptor CXCR3; and SM inhibited Treg TGIF1 transcript; (4) six genes upregulated in SM + M Tregs were matched with the top-ranked Th17 pathogenic genes; and 57, 39 genes upregulated in SM + M Tregs were matched with groups II and group III Th17 pathogenic genes, respectively; (5) SM + M upregulated the transcripts of 70 IPA-TFs, 11 iTregs-specific TFs, and 4 iTregs-Th17 shared TFs; and (6) SM + M, M, and SM downregulated Treg suppression TF Rel (c-Rel); and 35 SM + M downregulated genes were overlapped with Rel-/- Treg downregulated genes. These results provide novel insights on the roles of SM + M in reprogramming Treg transcriptomes and Treg plasticity to Th17 cells and novel targets for future therapeutic interventions involving immunosuppression in atherosclerotic cardiovascular diseases, autoimmune diseases, transplantation, and cancers.
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Affiliation(s)
- Ying Shao
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Fatma Saaoud
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - William Cornwell
- Center for Inflammation and Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Keman Xu
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Aaron Kirchhoff
- Center for Inflammation and Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Yifan Lu
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Xiaohua Jiang
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Thomas J. Rogers
- Center for Inflammation and Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Xiaofeng Yang
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Center for Inflammation and Lung Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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22
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Lee KM, Fu Q, Huai G, Deng K, Lei J, Kojima L, Agarwal D, Van Galen P, Kimura S, Tanimine N, Washburn L, Yeh H, Naji A, Rickert CG, LeGuern C, Markmann JF. Suppression of allograft rejection by regulatory B cells generated via toll-like receptor signaling. JCI Insight 2022; 7:152213. [PMID: 35943811 PMCID: PMC9536278 DOI: 10.1172/jci.insight.152213] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 07/28/2022] [Indexed: 11/20/2022] Open
Abstract
B lymphocytes have long been recognized for their critical contributions to adaptive immunity, providing defense against pathogens through cognate antigen presentation to T cells and Ab production. More recently appreciated is that B cells are also integral in securing self-tolerance; this has led to interest in their therapeutic application to downregulate unwanted immune responses, such as transplant rejection. In this study, we found that PMA- and ionomycin-activated mouse B cells acquire regulatory properties following stimulation through TLR4/TLR9 receptors (Bregs-TLR). Bregs-TLR efficiently inhibited T cell proliferation in vitro and prevented allograft rejection. Unlike most reported Breg activities, the inhibition of alloimmune responses by Bregs-TLR relied on the expression of TGF-β and not IL-10. In vivo, Bregs-TLR interrupted donor-specific T cell expansion and induced Tregs in a TGF-β–dependent manner. RNA-Seq analyses corroborated the involvement of TGF-β pathways in Breg-TLR function, identified potential gene pathways implicated in preventing graft rejection, and suggested targets to foster Breg regulation.
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Affiliation(s)
- Kang Mi Lee
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Qiang Fu
- Organ Transplantation Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Guoli Huai
- Organ Transplantation Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Kevin Deng
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Ji Lei
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Lisa Kojima
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Divyansh Agarwal
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, United States of America
| | - Peter Van Galen
- Division of Hematology, Brigham & Womans Hospital, Harvard Medical School, Boston, United States of America
| | - Shoko Kimura
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Naoki Tanimine
- Department of Gastroenterological and Transplantation Surgery, Hiroshima University, Hiroshima, Japan
| | - Laura Washburn
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Heidi Yeh
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Ali Naji
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, United States of America
| | - Charles G Rickert
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - Christian LeGuern
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
| | - James F Markmann
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America
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23
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Li L, Shirkey MW, Zhang T, Piao W, Li X, Zhao J, Mei Z, Guo Y, Saxena V, Kensiski A, Gavzy SJ, Song Y, Ma B, Wu J, Xiong Y, Wu L, Fan X, Roussey H, Li M, Krupnick AS, Abdi R, Bromberg JS. Lymph node fibroblastic reticular cells preserve a tolerogenic niche in allograft transplantation through laminin α4. J Clin Invest 2022; 132:e156994. [PMID: 35775481 PMCID: PMC9246384 DOI: 10.1172/jci156994] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 05/10/2022] [Indexed: 12/13/2022] Open
Abstract
Lymph node (LN) fibroblastic reticular cells (FRCs) define LN niches and regulate lymphocyte homeostasis through producing diverse extracellular matrix (ECM) components. We examined the role of ECM laminin α4 (Lama4) using FRC-Lama4 conditional KO Pdgfrb-Cre-/- × Lama4fl/fl mice. Single-cell RNA-sequencing (scRNA-Seq) data showed the promoter gene Pdgfrb was exclusively expressed in FRCs. Depleting FRC-Lama4 reduced Tregs and dendritic cells, decreased high endothelial venules, impaired the conduit system, and downregulated T cell survival factors in LNs. FRC-Lama4 depletion impaired the homing of lymphocytes to LNs in homeostasis and after allografting. Alloantigen-specific T cells proliferated, were activated to greater degrees in LNs lacking FRC-Lama4, and were more prone to differentiate into effector phenotypes relative to the Treg phenotype. In murine cardiac transplantation, tolerogenic immunosuppression was not effective in FRC-Lama4 recipients, which produced more alloantibodies than WT. After lung transplantation, FRC-Lama4-KO mice had more severe graft rejection with fewer Tregs in their LNs. Overall, FRC-Lama4 critically contributes to a tolerogenic LN niche by supporting T cell migration, constraining T cell activation and proliferation, and promoting Treg differentiation. Hence, it serves as a therapeutic target for immunoengineering.
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Affiliation(s)
- Lushen Li
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Marina W. Shirkey
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | - Wenji Piao
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiaofei Li
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jing Zhao
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Vikas Saxena
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Allison Kensiski
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Samuel J. Gavzy
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | - Bing Ma
- Institute for Genome Sciences
| | | | - Yanbao Xiong
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Long Wu
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiaoxuan Fan
- Flow Cytometry Shared Service, Greenebaum Comprehensive Cancer Center. and
| | | | - Meng Li
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | - Reza Abdi
- Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jonathan S. Bromberg
- Department of Surgery and
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
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24
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Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice. Int J Mol Sci 2022; 23:ijms23126433. [PMID: 35742877 PMCID: PMC9224120 DOI: 10.3390/ijms23126433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/06/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells.
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25
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Campos‐Mora M, De Solminihac J, Rojas C, Padilla C, Kurte M, Pacheco R, Kaehne T, Wyneken Ú, Pino‐Lagos K. Neuropilin-1 is present on Foxp3+ T regulatory cell-derived small extracellular vesicles and mediates immunity against skin transplantation. J Extracell Vesicles 2022; 11:e12237. [PMID: 35676234 PMCID: PMC9177693 DOI: 10.1002/jev2.12237] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/16/2022] [Accepted: 05/27/2022] [Indexed: 12/14/2022] Open
Abstract
Among the mechanisms of suppression that T regulatory (Treg) cells exert to control the immune responses, the secretion of small extracellular vesicles (sEV) has been recently proposed as a novel contact-independent immunomodulatory mechanism. Previous studies have demonstrated that Treg cells produce sEV, including exosomes, able to modulate the effector function of CD4+ T cells, and antigen presenting cells (APCs) such as dendritic cells (DCs) through the transfer of microRNA, cytokines, the production of adenosine, among others. Previously, we have demonstrated that Neuropilin-1 (Nrp1) is required for Tregs-mediated immunosuppression mainly by impacting on the phenotype and function of effector CD4+ T cells. Here, we show that Foxp3+ Treg cells secrete sEV, which bear Nrp1 in their membrane. These sEV modulate effector CD4+ T cell phenotype and proliferation in vitro in a Nrp1-dependent manner. Proteomic analysis indicated that sEV obtained from wild type (wt) and Nrp1KO Treg cells differed in proteins related to immune tolerance, finding less representation of CD73 and Granzyme B in sEV obtained from Nrp1KO Treg cells. Likewise, we show that Nrp1 is required in Treg cell-derived sEV for inducing skin transplantation tolerance, since a reduction in graft survival and an increase on M1/M2 ratio were found in animals treated with Nrp1KO Treg cell-derived sEV. Altogether, this study describes for the first time that Treg cells secrete sEV containing Nrp1 and that this protein, among others, is necessary to promote transplantation tolerance in vivo via sEV local administration.
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Affiliation(s)
- Mauricio Campos‐Mora
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
| | - Javiera De Solminihac
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
| | - Carolina Rojas
- Periodontal Biology LaboratoryFaculty of DentistryUniversidad de ChileSantiagoChile
| | - Cristina Padilla
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
| | - Mónica Kurte
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
| | - Rodrigo Pacheco
- Laboratorio de NeuroinmunologíaCentro Ciencia & VidaFundación Ciencia & VidaSantiagoChile
| | - Thilo Kaehne
- Institute of Experimental MedicineMedical FacultyOtto von Guericke UniversityMagdeburgGermany
| | - Úrsula Wyneken
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
| | - Karina Pino‐Lagos
- Centro de Investigación e Innovación BiomédicaFacultad de MedicinaUniversidad de los AndesSantiagoChile
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26
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Montazersaheb S, Ehsani A, Fathi E, Farahzadi R, Vietor I. An Overview of Autophagy in Hematopoietic Stem Cell Transplantation. Front Bioeng Biotechnol 2022; 10:849768. [PMID: 35677295 PMCID: PMC9168265 DOI: 10.3389/fbioe.2022.849768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Autophagy is a fundamental homeostatic process crucial for cellular adaptation in response to metabolic stress. Autophagy exerts its effect through degrading intracellular components and recycling them to produce macromolecular precursors and energy. This physiological process contributes to cellular development, maintenance of cellular/tissue homeostasis, immune system regulation, and human disease. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only preferred therapy for most bone marrow-derived cancers. Unfortunately, HSCT can result in several serious and sometimes untreatable conditions due to graft-versus-host disease (GVHD), graft failure, and infection. These are the major cause of morbidity and mortality in patients receiving the transplant. During the last decade, autophagy has gained a considerable understanding of its role in various diseases and cellular processes. In light of recent research, it has been confirmed that autophagy plays a crucial role in the survival and function of hematopoietic stem cells (HSCs), T-cell differentiation, antigen presentation, and responsiveness to cytokine stimulation. Despite the importance of these events to HSCT, the role of autophagy in HSCT as a whole remains relatively ambiguous. As a result of the growing use of autophagy-modulating agents in the clinic, it is imperative to understand how autophagy functions in allogeneic HSCT. The purpose of this literature review is to elucidate the established and implicated roles of autophagy in HSCT, identifying this pathway as a potential therapeutic target for improving transplant outcomes.
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Affiliation(s)
- Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Ehsani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ezzatollah Fathi
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Raheleh Farahzadi
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ilja Vietor
- Institute of Cell Biology, Medical University of Innsbruck, Biocenter, Innsbruck, Austria
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27
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Pohar J, O'Connor R, Manfroi B, Behi ME, Jouneau L, Boudinot P, Bunse M, Uckert W, Luka M, Ménager M, Liblau R, Anderton SM, Fillatreau S. Antigen receptor-engineered Tregs inhibit CNS autoimmunity in cell therapy using non-redundant immune mechanisms in mice. Eur J Immunol 2022; 52:1335-1349. [PMID: 35579560 PMCID: PMC9542066 DOI: 10.1002/eji.202249845] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/28/2022] [Accepted: 05/16/2022] [Indexed: 11/21/2022]
Abstract
CD4+FOXP3+ Tregs are currently explored to develop cell therapies against immune‐mediated disorders, with an increasing focus on antigen receptor‐engineered Tregs. Deciphering their mode of action is necessary to identify the strengths and limits of this approach. Here, we addressed this issue in an autoimmune disease of the CNS, EAE. Following disease induction, autoreactive Tregs upregulated LAG‐3 and CTLA‐4 in LNs, while IL‐10 and amphiregulin (AREG) were increased in CNS Tregs. Using genetic approaches, we demonstrated that IL‐10, CTLA‐4, and LAG‐3 were nonredundantly required for the protective function of antigen receptor‐engineered Tregs against EAE in cell therapy whereas AREG was dispensable. Treg‐derived IL‐10 and CTLA‐4 were both required to suppress acute autoreactive CD4+ T‐cell activation, which correlated with disease control. These molecules also affected the accumulation in the recipients of engineered Tregs themselves, underlying complex roles for these molecules. Noteworthy, despite the persistence of the transferred Tregs and their protective effect, autoreactive T cells eventually accumulated in the spleen of treated mice. In conclusion, this study highlights the remarkable power of antigen receptor‐engineered Tregs to appropriately provide multiple suppressive factors nonredundantly necessary to prevent autoimmune attacks.
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Affiliation(s)
- Jelka Pohar
- Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, 156-160, rue de Vaugirard, Paris, 75015, France
| | | | - Benoît Manfroi
- Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, 156-160, rue de Vaugirard, Paris, 75015, France
| | - Mohamed El Behi
- Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, 156-160, rue de Vaugirard, Paris, 75015, France
| | - Luc Jouneau
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, 78350, France
| | - Pierre Boudinot
- Université Paris-Saclay, INRAE, UVSQ, VIM, Jouy-en-Josas, 78350, France
| | - Mario Bunse
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Wolfgang Uckert
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Marine Luka
- Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, Paris, F-75015, France.,Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, F-75015, France
| | - Mickael Ménager
- Université de Paris, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, Paris, F-75015, France.,Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, F-75015, France
| | - Roland Liblau
- Infinity - Institut Toulousain des Maladies Infectieuses et Inflammatoires, NSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | | | - Simon Fillatreau
- Institut Necker Enfants Malades, Institut National de la Santé et de la Recherche Médicale INSERM U1151 - Centre National de la Recherche Scientifique CNRS UMR 8253, 156-160, rue de Vaugirard, Paris, 75015, France.,Université de Paris, Faculté de Médecine, Paris, France.,AP-HP, Hôpital Necker-Enfants Malades, Paris, France
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28
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Ding X, Le S, Wang K, Su Y, Chen S, Wu C, Chen J, Chen S, Zhang A, Xia J. Cytosporone B (Csn-B), an NR4A1 agonist, attenuates acute cardiac allograft rejection by inducing differential apoptosis of CD4+T cells. Int Immunopharmacol 2022; 104:108521. [PMID: 35026656 DOI: 10.1016/j.intimp.2022.108521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 11/16/2022]
Abstract
CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.
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Affiliation(s)
- Xiangchao Ding
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Sheng Le
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ke Wang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunshu Su
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shanshan Chen
- Key Laboratory for Molecular Diagnosis of Hubei Province and Central Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuangyan Wu
- Departments of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiuling Chen
- Departments of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanshan Chen
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Anchen Zhang
- Department of Cardiovascular Medicine, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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29
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Gan X, Gu J, Ju Z, Lu L. Diverse Roles of Immune Cells in Transplant Rejection and Immune Tolerance. ENGINEERING 2022; 10:44-56. [DOI: 10.1016/j.eng.2021.03.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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30
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Bernaldo-de-Quirós E, Pion M, Martínez-Bonet M, Correa-Rocha R. A New Generation of Cell Therapies Employing Regulatory T Cells (Treg) to Induce Immune Tolerance in Pediatric Transplantation. Front Pediatr 2022; 10:862807. [PMID: 35633970 PMCID: PMC9130702 DOI: 10.3389/fped.2022.862807] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
Kidney transplantation is the most common solid organ transplant and the preferred treatment for pediatric patients with end-stage renal disease, but it is still not a definitive solution due to immune graft rejection. Regulatory T cells (Treg) and their control over effector T cells is a crucial and intrinsic tolerance mechanism in limiting excessive immune responses. In the case of transplants, Treg are important for the survival of the transplanted organ, and their dysregulation could increase the risk of rejection in transplanted children. Chronic immunosuppression to prevent rejection, for which Treg are especially sensitive, have a detrimental effect on Treg counts, decreasing the Treg/T-effector balance. Cell therapy with Treg cells is a promising approach to restore this imbalance, promoting tolerance and thus increasing graft survival. However, the strategies used to date that employ peripheral blood as a Treg source have shown limited efficacy. Moreover, it is not possible to use this approach in pediatric patients due to the limited volume of blood that can be extracted from children. Here, we outline our innovative strategy that employs the thymus removed during pediatric cardiac surgeries as a source of therapeutic Treg that could make this therapy accessible to transplanted children. The advantageous properties and the massive amount of Treg cells obtained from pediatric thymic tissue (thyTreg) opens a new possibility for Treg therapies to prevent rejection in pediatric kidney transplants. We are recruiting patients in a clinical trial to prevent rejection in heart-transplanted children through the infusion of autologous thyTreg cells (NCT04924491). If its efficacy is confirmed, thyTreg therapy may establish a new paradigm in preventing organ rejection in pediatric transplants, and their allogeneic use would extend its application to other solid organ transplantation.
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Affiliation(s)
- Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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31
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Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD. Blood Adv 2021; 5:4578-4589. [PMID: 34619767 PMCID: PMC8759141 DOI: 10.1182/bloodadvances.2020001514] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 09/02/2021] [Indexed: 01/01/2023] Open
Abstract
Weekly infusions of third-party ILC2s prevent, and to a lesser extent, treat GVHD via production of IL-13 and amphiregulin. ILC2-derived IL-13 targets both host cells and the donor hematopoietic cells. Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an “off-the-shelf” reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.
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Green S, Politis M, Rallis KS, Saenz de Villaverde Cortabarria A, Efthymiou A, Mureanu N, Dalrymple KV, Scottà C, Lombardi G, Tribe RM, Nicolaides KH, Shangaris P. Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis. Front Immunol 2021; 12:737862. [PMID: 34777347 PMCID: PMC8586555 DOI: 10.3389/fimmu.2021.737862] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022] Open
Abstract
Background Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes. Objective The aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB). Method Literature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed. Results From 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03-1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13-1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79-0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34-5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations. Conclusion Lower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link. Systematic Review Registration PROSPERO, identifier CRD42020205469.
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Affiliation(s)
- Samantha Green
- University of Aberdeen School of Medicine and Dentistry, University of Aberdeen, Aberdeen, United Kingdom
| | - Marina Politis
- Undergraduate Medical School, University of Glasgow, Glasgow, United Kingdom
| | - Kathrine S. Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | | | - Athina Efthymiou
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
| | - Nicoleta Mureanu
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
| | - Kathryn V. Dalrymple
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
| | - Cristiano Scottà
- School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
| | - Giovanna Lombardi
- School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
| | - Rachel M. Tribe
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
| | - Kypros H. Nicolaides
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
| | - Panicos Shangaris
- Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine King’s College London, London, United Kingdom
- School of Immunology & Microbial Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
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Ezzelarab MB, Zhang H, Sasaki K, Lu L, Zahorchak AF, van der Windt DJ, Dai H, Perez-Gutierrez A, Bhama JK, Thomson AW. Ex Vivo Expanded Donor Alloreactive Regulatory T Cells Lose Immunoregulatory, Proliferation, and Antiapoptotic Markers After Infusion Into ATG-lymphodepleted, Nonhuman Primate Heart Allograft Recipients. Transplantation 2021; 105:1965-1979. [PMID: 33587433 PMCID: PMC8239063 DOI: 10.1097/tp.0000000000003617] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.
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Affiliation(s)
- Mohamed B. Ezzelarab
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hong Zhang
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kazuki Sasaki
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Lien Lu
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Alan F. Zahorchak
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Dirk J. van der Windt
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Helong Dai
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Angelica Perez-Gutierrez
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jay K. Bhama
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Angus W. Thomson
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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34
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Lan X, Hu YH, Li X, Kong DJ, Qin YF, Wang H. Oxymatrine protects cardiac allografts by regulating immunotolerant cells. Int Immunopharmacol 2021; 100:108080. [PMID: 34454287 DOI: 10.1016/j.intimp.2021.108080] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 08/13/2021] [Accepted: 08/15/2021] [Indexed: 11/28/2022]
Abstract
Organ transplantation is an effective treatment strategy for patients with irreversible organ failure or congenital organ dysfunction. Oxymatrine (OMT) is a quinolizidine alkaloid with protective and anti-inflammatory effects on tissues and organs. The objective of this study was to investigate whether OMT could exert protective effects in cardiac allografts by regulating immune cells. In vitro cell proliferation and co-culture experiments were used to measure the effects of OMT on splenocyte proliferation and differentiation. In the in vivo study, C57BL/6 mice transplanted with BALB/c cardiac grafts were randomly divided into untreated, low-dose OMT treated, middle-dose OMT treated, high-dose OMT treated, and rapamycin-treated groups. Haematoxylin and eosin and immunohistochemical staining were used to assess pathological changes in the grafts, and fluorescence-activated cell sorting analysis was performed to measure the percentages of immune cells. The results showed that, in the in vitro study, OMT inhibited splenocyte proliferation, decreased the percentage of mature dendritic cells (DCs), and increased the percentage of regulatory T cells (Tregs) and regulatory B cells (Bregs). In the in vivo study, OMT exerted allograft protective effects by prolonging survival time, alleviating pathological damages to the cardiac allograft, decreasing intragraft CD3+ cell and increasing intragraft Foxp3+ cell infiltration, decreasing the percentages of mature DCs, increasing the percentages of Tregs and Bregs, and inhibiting the function of DCs. In conclusion, our study demonstrates that OMT exerted a protective effect on cardiac allografts by regulating immunotolerant cells. More in-depth studies of OMT may provide additional insight into the use of immunosuppressive drugs as a post-transplantation treatment strategy.
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Affiliation(s)
- Xu Lan
- Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Yong-Hao Hu
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Xiang Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - De-Jun Kong
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Ya-Fei Qin
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China
| | - Hao Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China; Tianjin General Surgery Institute, Tianjin, China.
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35
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Liu G, Liu M, Wang J, Mou Y, Che H. The Role of Regulatory T Cells in Epicutaneous Immunotherapy for Food Allergy. Front Immunol 2021; 12:660974. [PMID: 34305893 PMCID: PMC8297384 DOI: 10.3389/fimmu.2021.660974] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
In recent decades, a rapid increase in the prevalence of food allergies has led to extensive research on novel treatment strategies and their mechanisms. Mouse models have provided preliminary insights into the mechanism of epicutaneous immunotherapy (EPIT)-induced immune tolerance. In EPIT, antigen applied on the skin surface can be captured, processed, and presented in the lymph nodes (LNs) by Antigen-presenting cells (APCs). In the LNs, induction of regulatory T cells (Treg cells) requires both direct contact during antigen presentation and indirect mechanisms such as cytokines. Foxp3+CD62L+ Treg cells can exhibit the characteristics of hypomethylation of Foxp3 TSDR and Foxp3-LAP+ Treg cells, which increase the expression of surface tissue-specific homing molecules to exert further sustained systemic immune tolerance. Studies have shown that EPIT is a potential treatment for food allergies and can effectively induce immune tolerance, but its mechanism needs further exploration. Here, we review Treg cells' role in immune tolerance induced by EPIT and provide a theoretical basis for future research directions, such as the mechanism of EPIT and the development of more effective EPIT treatments.
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Affiliation(s)
| | | | | | | | - Huilian Che
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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36
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Liu H, Yu Z, Tang B, Miao S, Qin C, Li Y, Liang Z, Shi Y, Zhang Y, Wang Q, Yan M, Song Z, Ren H, Dong Y. LYG1 Deficiency Attenuates the Severity of Acute Graft-Versus-Host Disease via Skewing Allogeneic T Cells Polarization Towards Treg Cells. Front Immunol 2021; 12:647894. [PMID: 34262560 PMCID: PMC8273552 DOI: 10.3389/fimmu.2021.647894] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 06/11/2021] [Indexed: 11/13/2022] Open
Abstract
Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.
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Affiliation(s)
- Huihui Liu
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Zhengyu Yu
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Bo Tang
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Shengchao Miao
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Chenchen Qin
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Yuan Li
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Zeyin Liang
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Yongjin Shi
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Yang Zhang
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Qingya Wang
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Miao Yan
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Zhengyang Song
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Hanyun Ren
- Department of Hematology, Peking University First Hospital, Beijing, China
| | - Yujun Dong
- Department of Hematology, Peking University First Hospital, Beijing, China
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37
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Petrus-Reurer S, Romano M, Howlett S, Jones JL, Lombardi G, Saeb-Parsy K. Immunological considerations and challenges for regenerative cellular therapies. Commun Biol 2021; 4:798. [PMID: 34172826 PMCID: PMC8233383 DOI: 10.1038/s42003-021-02237-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The central goal of regenerative medicine is to replace damaged or diseased tissue with cells that integrate and function optimally. The capacity of pluripotent stem cells to produce unlimited numbers of differentiated cells is of considerable therapeutic interest, with several clinical trials underway. However, the host immune response represents an important barrier to clinical translation. Here we describe the role of the host innate and adaptive immune responses as triggers of allogeneic graft rejection. We discuss how the immune response is determined by the cellular therapy. Additionally, we describe the range of available in vitro and in vivo experimental approaches to examine the immunogenicity of cellular therapies, and finally we review potential strategies to ameliorate immune rejection. In conclusion, we advocate establishment of platforms that bring together the multidisciplinary expertise and infrastructure necessary to comprehensively investigate the immunogenicity of cellular therapies to ensure their clinical safety and efficacy.
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Affiliation(s)
- Sandra Petrus-Reurer
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
| | - Marco Romano
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Sarah Howlett
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Joanne Louise Jones
- Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Giovanna Lombardi
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
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38
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Ni X, Wang Q, Gu J, Lu L. Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:535012. [PMID: 34093514 PMCID: PMC8173171 DOI: 10.3389/fimmu.2021.535012] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 04/26/2021] [Indexed: 12/29/2022] Open
Abstract
Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.
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Affiliation(s)
- Xuhao Ni
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Qi Wang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Jian Gu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
| | - Ling Lu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China.,Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.,Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China
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39
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PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLoS Biol 2021; 19:e3001199. [PMID: 33901179 PMCID: PMC8101994 DOI: 10.1371/journal.pbio.3001199] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 05/06/2021] [Accepted: 03/22/2021] [Indexed: 12/17/2022] Open
Abstract
Programmed cell death protein 1 (PD-1) is expressed on T cells upon T cell receptor (TCR) stimulation. PD-1 ligand 1 (PD-L1) is expressed in most tumor environments, and its binding to PD-1 on T cells drives them to apoptosis or into a regulatory phenotype. The fact that PD-L1 itself is also expressed on T cells upon activation has been largely neglected. Here, we demonstrate that PD-L1 ligation on human CD25-depleted CD4+ T cells, combined with CD3/TCR stimulation, induces their conversion into highly suppressive T cells. Furthermore, this effect was most prominent in memory (CD45RA−CD45RO+) T cells. PD-L1 engagement on T cells resulted in reduced ERK phosphorylation and decreased AKT/mTOR/S6 signaling. Importantly, T cells from rheumatoid arthritis patients exhibited high basal levels of phosphorylated ERK and following PD-L1 cross-linking both ERK signaling and the AKT/mTOR/S6 pathway failed to be down modulated, making them refractory to the acquisition of a regulatory phenotype. Altogether, our results suggest that PD-L1 signaling on memory T cells could play an important role in resolving inflammatory responses; maintaining a tolerogenic environment and its failure could contribute to ongoing autoimmunity. This study shows that programmed death cell receptor ligand 1 (PD-L1) signaling in memory CD4+ T cells from healthy individuals induces a regulatory phenotype; this mechanism seems to be defective in equivalent T cells from rheumatoid arthritis patients and could be in part responsible for the pathology.
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40
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The Presence of a Marked Imbalance Between Regulatory T Cells and Effector T Cells Reveals That Tolerance Mechanisms Could Be Compromised in Heart Transplant Children. Transplant Direct 2021; 7:e693. [PMID: 33928185 PMCID: PMC8078462 DOI: 10.1097/txd.0000000000001152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/05/2021] [Accepted: 03/06/2021] [Indexed: 12/19/2022] Open
Abstract
Regulatory T cells (Treg) are crucial for the induction and maintenance of graft tolerance. In pediatric heart transplant procedures, the thymus is routinely excised, removing the primary source of T-cell replenishment. Consequently, thymectomy joined to the effects of immunosuppression on the T-cell compartment may have a detrimental impact on Treg values, compromising the intrinsic tolerance mechanisms and the protective role of Treg preventing graft rejection in heart transplant children.
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41
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Treg sensitivity to FasL and relative IL-2 deprivation drive idiopathic aplastic anemia immune dysfunction. Blood 2021; 136:885-897. [PMID: 32294156 DOI: 10.1182/blood.2019001347] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
Idiopathic aplastic anemia (AA) has 2 key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T-cells (Tregs) deficiency. We have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predicts response to immunosuppression. The aims of the present study were to define mechanisms of Treg subpopulation imbalance and identify potential for therapeutic intervention. We have identified 2 mechanisms that lead to skewed Treg composition in AA: first, FasL-mediated apoptosis on ligand interaction; and, second, relative interleukin-2 (IL-2) deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed a high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T-cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions. Supplementation of ex vivo expansion cultures of Tregs with high concentrations of IL-2 or delivery of IL-2 directly to patients could improve clinical outcomes in addition to standard immunosuppressive therapy.
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42
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Marfil-Garza BA, Hefler J, Bermudez De Leon M, Pawlick R, Dadheech N, Shapiro AMJ. Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation. Endocr Rev 2021; 42:198-218. [PMID: 33247733 DOI: 10.1210/endrev/bnaa028] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.
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Affiliation(s)
| | - Joshua Hefler
- Department of Surgery, University of Alberta, Edmonton, Canada
| | - Mario Bermudez De Leon
- Department of Molecular Biology, Centro de Investigación Biomédica del Noreste, Instituto Mexicano del Seguro Social, Monterrey, Nuevo Leon, Mexico
| | - Rena Pawlick
- Department of Surgery, University of Alberta, Edmonton, Canada
| | | | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Canada.,Clinical Islet Transplant Program, University of Alberta, Edmonton, Canada
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43
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Tsai H, Zeng X, Liu L, Xin S, Wu Y, Xu Z, Zhang H, Liu G, Bi Z, Su D, Yang M, Tao Y, Wang C, Zhao J, Eriksson JE, Deng W, Cheng F, Chen H. NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development. EMBO Mol Med 2021; 13:e12834. [PMID: 33555115 PMCID: PMC7933818 DOI: 10.15252/emmm.202012834] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 12/26/2020] [Accepted: 01/04/2021] [Indexed: 12/31/2022] Open
Abstract
Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2-like sequences in rDNA promoter upon T-cell activation in vitro. The elevated pre-rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T-cell activation can be significantly suppressed by inhibiting NF45/NF90-dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription-specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off-target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90-mediated rDNA transcription as a novel signaling pathway essential for T-cell activation and as a new target for the development of safe and effective immunosuppressants.
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Affiliation(s)
- Hsiang‐i Tsai
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Xiaobin Zeng
- Center Lab of Longhua Branch and Department of Infectious DiseaseShenzhen People's Hospital2 Clinical Medical College of Jinan UniversityShenzhenChina
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesMedicine School of Shenzhen UniversityShenzhenChina
| | - Longshan Liu
- Organ Transplant CentermThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shengchang Xin
- State Key Laboratory of Coordination ChemistryInstitute of Chemistry and Biomedical SciencesSchool of Life SciencesNanjing UniversityNanjingChina
| | - Yingyi Wu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Zhanxue Xu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Huanxi Zhang
- Organ Transplant CentermThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Gan Liu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Zirong Bi
- Organ Transplant CentermThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Dandan Su
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Min Yang
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Yijing Tao
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Changxi Wang
- Organ Transplant CentermThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jing Zhao
- State Key Laboratory of Coordination ChemistryInstitute of Chemistry and Biomedical SciencesSchool of Life SciencesNanjing UniversityNanjingChina
| | - John E Eriksson
- Cell BiologyBiosciencesFaculty of Science and EngineeringÅbo Akademi UniversityTurkuFinland
- Turku Centre for BiotechnologyUniversity of Turku and Åbo Akademi UniversityTurkuFinland
| | - Wenbin Deng
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Fang Cheng
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐Sen UniversityShenzhenChina
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44
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Kuwabara R, Hu S, Smink AM, Orive G, Lakey JRT, de Vos P. Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:129-140. [PMID: 33397201 DOI: 10.1089/ten.teb.2020.0326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.
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Affiliation(s)
- Rei Kuwabara
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuxian Hu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Jonathan R T Lakey
- Department of Surgery and Biomedical Engineering, University of California Irvine, Irvine, California, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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45
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Ogata K, Matsumura-Kawashima M, Moriyama M, Kawado T, Nakamura S. Dental pulp-derived stem cell-conditioned media attenuates secondary Sjögren's syndrome via suppression of inflammatory cytokines in the submandibular glands. Regen Ther 2021; 16:73-80. [PMID: 33659580 PMCID: PMC7878993 DOI: 10.1016/j.reth.2021.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 01/01/2021] [Accepted: 01/16/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease, which affects the exocrine glands. Its primary symptoms are decreased moisture in the mouth and eyes. Therapies are limited to treatment with steroids, which has unpleasant side effects, so new treatments would be beneficial. One possibility might be stem cells, such as bone marrow mesenchymal stem cells (BMMSCs) or dental pulp-derived stem cells (DPSCs); these have been reported to exert immunomodulatory effects on activated lymphoid cells. This study aimed to evaluate the effects of conditioned media from DPSCs (DPSC-CM) or BMMSCs (BMMSC-CM) on salivary functions in SS. Methods Cytokine array analysis was performed to assess the types of cytokines present in the media. DPSC-CM or BMMSC-CM was administered in an SS mouse model. Histological analysis of the salivary glands was performed, and gene expression levels of inflammatory and anti-inflammatory cytokines in the submandibular glands (SMGs) were evaluated. Results DPSC-CM contained more anti-inflammatory factors than BMMSC-CM. The mice that were given DPSC-CM had a lower number of inflammation sites in the SMGs than those in the other experimental groups, and their salivary flow rate increased. The expression levels of interleukin (IL)-10 and transforming growth factor-β1 increased in the DPSC-CM group, while those of Il-4, Il-6, and Il-17a decreased. The mice that received DPSC-CM showed a significantly increased percentage of regulatory T cells and a significantly decreased percentage of type T helper 17 cells compared to other groups. Conclusions These results indicate that DPSC-CM could be an effective therapy for SS-induced hyposalivation, since it decreases the number of inflammatory cytokines and regulates the local inflammatory microenvironment in the SMGs.
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Andres AM, Stringa P, Talayero P, Santamaria M, García-Arranz M, García Gómez-Heras S, Largo-Aramburu C, Aras-Lopez RM, Vallejo-Cremades MT, Guerra Pastrián L, Vega L, Encinas JL, Lopez-Santamaria M, Hernández-Oliveros F. Graft infusion of adipose-derived mesenchymal stromal cells to prevent rejection in experimental intestinal transplantation: A feasibility study. Clin Transplant 2021; 35:e14226. [PMID: 33465824 DOI: 10.1111/ctr.14226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose-derived MSC (Ad-MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). MATERIAL/METHODS Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad-MSC was intra-arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad-MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad-MSC (TAC_MSC) groups. Each Ad-MSC groups was subdivided in autologous and allogeneic third-party groups. RESULTS Rejection rate and severity were similar in MSC-treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T-cell (CD4, CD8, and Foxp3 subsets) and B-cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro- and anti-inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. CONCLUSION Ad-MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer-term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies.
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Affiliation(s)
- Ane M Andres
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain.,Idipaz Institute, La Paz University Hospital, Madrid, Spain.,TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | - Pablo Stringa
- Institute for Immunological and Physiopathological Studies (IIFP-CONICET-UNLP), National University of La Plata, Buenos Aires, Argentina
| | - Paloma Talayero
- Immunology Department, 12 de Octubre University Hospital, Madrid, Spain.,imas12 Research Institute, 12 de Octubre University Hospital, Madrid, Spain
| | - Monica Santamaria
- Experimental Transplant Department, Alfonso X University, Madrid, Spain
| | | | | | | | - Rosa M Aras-Lopez
- Research Institute, Idipaz Institute, La Paz University Hospital, Madrid, Spain
| | | | | | - Luz Vega
- Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain
| | - Jose Luis Encinas
- Pediatric Surgery Department, La Paz University Hospital, Madrid, Spain
| | | | - Francisco Hernández-Oliveros
- TransplantChild ERN, Idipaz Institute, La Paz University Hospital, Madrid, Spain.,Health Research Institute, Fundación Jimenez Diaz, Madrid, Spain.,Pediatric Surgery Department EOC TransplantChild ERN, La Paz University Hospital, Madrid, Spain
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Pathak S, Meyer EH. Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation. Front Immunol 2021; 11:612737. [PMID: 33658995 PMCID: PMC7917336 DOI: 10.3389/fimmu.2020.612737] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 12/14/2020] [Indexed: 01/07/2023] Open
Abstract
Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize Tregs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since Tregs play a critical role in the establishment of mixed chimerism, it follows that the combination of Treg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using Tregs and/or hematopoietic mixed chimerism are underway or being formulated.
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Affiliation(s)
- Shiva Pathak
- Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States
| | - Everett H. Meyer
- Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, United States
- Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States
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48
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Bayati F, Mohammadi M, Valadi M, Jamshidi S, Foma AM, Sharif-Paghaleh E. The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities. Front Immunol 2021; 11:585819. [PMID: 33519807 PMCID: PMC7844143 DOI: 10.3389/fimmu.2020.585819] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 11/27/2020] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) are an immunosuppressive subgroup of CD4+ T cells which are identified by the expression of forkhead box protein P3 (Foxp3). The modulation capacity of these immune cells holds an important role in both transplantation and the development of autoimmune diseases. These cells are the main mediators of self-tolerance and are essential for avoiding excessive immune reactions. Tregs play a key role in the induction of peripheral tolerance that can prevent autoimmunity, by protecting self-reactive lymphocytes from the immune reaction. In contrast to autoimmune responses, tumor cells exploit Tregs in order to prevent immune cell recognition and anti-tumor immune response during the carcinogenesis process. Recently, numerous studies have focused on unraveling the biological functions and principles of Tregs and their primary suppressive mechanisms. Due to the promising and outstanding results, Tregs have been widely investigated as an alternative tool in preventing graft rejection and treating autoimmune diseases. On the other hand, targeting Tregs for the purpose of improving cancer immunotherapy is being intensively evaluated as a desirable and effective method. The purpose of this review is to point out the characteristic function and therapeutic potential of Tregs in regulatory immune mechanisms in transplantation tolerance, autoimmune diseases, cancer therapy, and also to discuss that how the manipulation of these mechanisms may increase the therapeutic options.
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Affiliation(s)
- Fatemeh Bayati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research & Development Department, Aryogen Pharmed, Karaj, Iran
| | - Mahsa Mohammadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Maryam Valadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Jamshidi
- Research & Development Department, Aryogen Pharmed, Karaj, Iran
| | - Arron Munggela Foma
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Sharif-Paghaleh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
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Gao J, Geng R, Deng H, Zuo H, Weng S, He J, Xu X. A Novel Forkhead Box Protein P (FoxP) From Litopenaeus vannamei Plays a Positive Role in Immune Response. Front Immunol 2021; 11:593987. [PMID: 33381114 PMCID: PMC7768020 DOI: 10.3389/fimmu.2020.593987] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/04/2020] [Indexed: 11/22/2022] Open
Abstract
The forkhead box protein P (FoxP) family members have been known to be important for regulation of immune responses in vertebrates, but their roles in invertebrate immunity remain unclear. In this study, a novel FoxP gene (LvFoxP) was identified from Pacific white shrimp Litopenaeus vannamei and functionally studied in the context of immune response. Possessing a conserved FoxP coiled-coil domain and a forkhead domain, LvFoxP shared homology to vertebrate FoxP family members, in particular FoxP1. Expression of LvFoxP was detectable in all the examined tissues and could be up-regulated by immune challenge in gill and hemocytes. The LvFoxP protein was present in both the cytoplasm and nucleus of hemocytes and could be nuclear-translocated upon immune stimulation. Silencing of LvFoxP increased the susceptibility of shrimp to infections by Vibrio parahaemolyticus and white spot syndrome virus (WSSV) and down-regulated the expression of multiple components of NF-κB and JAK-STAT pathways and almost all the examined immune effector genes. Moreover, the phagocytic activity of hemocytes from LvFoxP-silenced shrimp against V. parahaemolyticus was decreased. These suggested that LvFoxP could play a positive role in immune response. The current study may provide novel insights into the immunity of invertebrates and the functional evolution of the FoxP family.
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Affiliation(s)
- Jiefeng Gao
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China
| | - Ran Geng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China
| | - Hengwei Deng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.,Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, China
| | - Hongliang Zuo
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.,Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, China
| | - Shaoping Weng
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.,Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, China
| | - Jianguo He
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.,Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, China
| | - Xiaopeng Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.,Institute of Aquatic Economic Animals and Guangdong Provice Key Laboratory for Aquatic Economic Animals, Sun Yat-sen University, Guangzhou, China
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50
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Kolb HR, Borcherding N, Zhang W. Understanding and Targeting Human Cancer Regulatory T Cells to Improve Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:229-256. [PMID: 33523451 DOI: 10.1007/978-981-15-6407-9_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Tregs) are critical in maintaining immune homeostasis under various pathophysiological conditions. A growing body of evidence demonstrates that Tregs play an important role in cancer progression and that they do so by suppressing cancer-directed immune responses. Tregs have been targeted for destruction by exploiting antibodies against and small-molecule inhibitors of several molecules that are highly expressed in Tregs-including immune checkpoint molecules, chemokine receptors, and metabolites. To date, these strategies have had only limited antitumor efficacy, yet they have also created significant risk of autoimmunity because most of them do not differentiate Tregs in tumors from those in normal tissues. Currently, immune checkpoint inhibitor (ICI)-based cancer immunotherapies have revolutionized cancer treatment, but the resistance to ICI is common and the elevation of Tregs is one of the most important mechanisms. Therapeutic strategies that can selectively eliminate Tregs in the tumor (i.e. therapies that do not run the risk of causing autoimmunity by affecting normal tissue), are urgently needed for the development of cancer immunotherapies. This chapter discusses specific properties of human Tregs under the context of cancer and the various ways to target Treg for cancer immunotherapy.
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Affiliation(s)
- H Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Nicholas Borcherding
- Department of Pathology and Immunology, Washington University, St. Louis, MO, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
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