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Syed Khaja AS, Binsaleh NK, Qanash H, Alshetaiwi H, Ginawi IAM, Saleem M. Dysregulation and therapeutic prospects of regulatory T cells in type 1 diabetes. Acta Diabetol 2025:10.1007/s00592-025-02478-3. [PMID: 40116924 DOI: 10.1007/s00592-025-02478-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 02/19/2025] [Indexed: 03/23/2025]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys β-cells in the pancreas that produce insulin. Several studies have implicated and elaborated the significant role of regulatory T cells (Tregs) in the pathogenesis of T1D. Tregs are a specialized subset of T cells and are critical regulators of peripheral self-tolerance. However, if the number, function, or stability of these cells is altered, it can lead to autoimmunity. This review summarizes the current knowledge and understanding about Treg function in both health and T1D, Tregs dysregulation, and various factors, including microRNAs, that affect their dysregulation in T1D. The review also focuses on the advantages and challenges of Treg-based therapies for T1D.
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Affiliation(s)
- Azharuddin Sajid Syed Khaja
- Department of Pathology, College of Medicine, University of Hail, 55476, Hail, Saudi Arabia.
- Medical and Diagnostic Research Centre, University of Hail, 55476, Hail, Saudi Arabia.
| | - Naif K Binsaleh
- Medical and Diagnostic Research Centre, University of Hail, 55476, Hail, Saudi Arabia
- Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Hail, 55476, Hail, Saudi Arabia
| | - Husam Qanash
- Medical and Diagnostic Research Centre, University of Hail, 55476, Hail, Saudi Arabia
- Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Hail, 55476, Hail, Saudi Arabia
| | - Hamad Alshetaiwi
- Department of Pathology, College of Medicine, University of Hail, 55476, Hail, Saudi Arabia
- Medical and Diagnostic Research Centre, University of Hail, 55476, Hail, Saudi Arabia
| | | | - Mohd Saleem
- Department of Pathology, College of Medicine, University of Hail, 55476, Hail, Saudi Arabia
- Medical and Diagnostic Research Centre, University of Hail, 55476, Hail, Saudi Arabia
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2
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Shapiro MR, Tallon EM, Brown ME, Posgai AL, Clements MA, Brusko TM. Leveraging artificial intelligence and machine learning to accelerate discovery of disease-modifying therapies in type 1 diabetes. Diabetologia 2025; 68:477-494. [PMID: 39694914 PMCID: PMC11832708 DOI: 10.1007/s00125-024-06339-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/28/2024] [Indexed: 12/20/2024]
Abstract
Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the 'gold standard' of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning to accelerate drug discovery and efficacy testing. Here, we review emerging approaches for repurposing agents used to treat diseases that share pathogenic pathways with type 1 diabetes and selecting synergistic combinations of drugs to maximise therapeutic efficacy. We discuss how emerging multi-omics technologies, including analysis of antigen processing and presentation to adaptive immune cells, may lead to the discovery of novel biomarkers and subsequent translation into antigen-specific immunotherapies. We also discuss the potential for using artificial intelligence to create 'digital twin' models that enable rapid in silico testing of personalised agents as well as dose determination. To conclude, we discuss some limitations of artificial intelligence and machine learning, including issues pertaining to model interpretability and bias, as well as the continued need for validation studies via confirmatory intervention trials.
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Affiliation(s)
- Melanie R Shapiro
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Erin M Tallon
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- Institute for Data Science and Informatics, University of Missouri-Columbia, Columbia, MO, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Matthew E Brown
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
- Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Mark A Clements
- Division of Pediatric Endocrinology and Diabetes, Children's Mercy Kansas City, Kansas City, MO, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Todd M Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
- Diabetes Institute, University of Florida, Gainesville, FL, USA.
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
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3
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Ramón-Vázquez A, Flood P, Cashman TL, Patil P, Ghosh S. T lymphocyte plasticity in chronic inflammatory diseases: The emerging role of the Ikaros family as a key Th17-Treg switch. Autoimmun Rev 2025; 24:103735. [PMID: 39719186 DOI: 10.1016/j.autrev.2024.103735] [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: 08/13/2024] [Revised: 12/14/2024] [Accepted: 12/20/2024] [Indexed: 12/26/2024]
Abstract
T helper (Th) 17 and regulatory T (Treg) cells are highly plastic CD4+ Th cell subsets, being able not only to actively adapt to their microenvironment, but also to interconvert, acquiring mixed identity markers. These phenotypic changes are underpinned by transcriptional control mechanisms, chromatin reorganization events and epigenetic modifications, that can be hereditable and stable over time. The Ikaros family of transcription factors have a predominant role in T cell subset specification through mechanisms of transcriptional program regulation that enable phenotypical diversification. They are crucial factors in maintaining Th17/Treg balance and therefore, homeostatic conditions in the tissues. However, they are also implicated in pathogenic processes, where their transcriptional repression contributes to the control of autoimmune processes. In this review, we discuss how T cell fate, specifically in humans, is regulated by the Ikaros family and its interplay with additional factors like the Notch signaling pathway, gut microbiota and myeloid-T cell interactions. Further, we highlight how the transcriptional activity of the Ikaros family impacts the course of T cell mediated chronic inflammatory diseases like rheumatoid and psoriatic arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. We conclude by discussing recently developed therapeutics designed to target Ikaros family members.
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Affiliation(s)
| | - P Flood
- APC Microbiome Ireland, University College Cork, Ireland
| | - T L Cashman
- APC Microbiome Ireland, University College Cork, Ireland
| | - P Patil
- APC Microbiome Ireland, University College Cork, Ireland
| | - S Ghosh
- APC Microbiome Ireland, University College Cork, Ireland; College of Medicine and Health, University College Cork, Ireland
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4
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Mondal S, Pappachan JM. Current perspectives and the future of disease-modifying therapies in type 1 diabetes. World J Diabetes 2025; 16:99496. [PMID: 39817218 PMCID: PMC11718456 DOI: 10.4239/wjd.v16.i1.99496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 10/11/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Use of immunomodulating agents to prevent the progression of autoimmune β-cell damage leading to type 1 diabetes mellitus (T1DM) is an interesting area for research. These include non-specific anti-inflammatory agents, immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines. Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen. Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM. The benefits have been apparent as early as six months to as long as seven years after therapy. It has recently been approved by the Food and Drug Administration to delay the onset of clinical (stage 3) type 1 diabetes in children above 8 years of age. In their recent meta-analysis published in the World Journal of Diabetes, Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use, change in C-peptide response, and better glycemic control compared to the control group with a good safety profile. However, all the included randomized control trials have been conducted in high-income countries. High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.
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Affiliation(s)
- Sunetra Mondal
- Department of Endocrinology, NRS Medical College and Hospital, Kolkata 700014, West Bengal, India
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal 576104, India
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Huang Q, Zhu J. Regulatory T cell-based therapy in type 1 diabetes: Latest breakthroughs and evidence. Int Immunopharmacol 2024; 140:112724. [PMID: 39098233 DOI: 10.1016/j.intimp.2024.112724] [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: 06/07/2024] [Revised: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 08/06/2024]
Abstract
Autoimmune diseases (ADs) are among the most significant health complications, with their incidence rising in recent years. Type 1 diabetes (T1D), an AD, targets the insulin-producing β cells in the pancreas, leading to chronic insulin deficiency in genetically susceptible individuals. Regulatory immune cells, particularly T-cells (Tregs), have been shown to play a crucial role in the pathogenesis of diabetes by modulating immune responses. In diabetic patients, Tregs often exhibit diminished effectiveness due to various factors, such as instability in forkhead box P3 (Foxp3) expression or abnormal production of the proinflammatory cytokine interferon-gamma (IFN-γ) by autoreactive T-cells. Consequently, Tregs represent a potential therapeutic target for diabetes treatment. Building on the successful clinical outcomes of chimeric antigen receptor (CAR) T-cell therapy in cancer treatment, particularly in leukemias, the concept of designing and utilizing CAR Tregs for ADs has emerged. This review summarizes the findings on Treg targeting in T1D and discusses the benefits and limitations of this treatment approach for patients suffering from T1D.
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Affiliation(s)
- Qiongxiao Huang
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
| | - Jing Zhu
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.
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Luo Z, Mejia-Cordova M, Hamze N, Berggren E, Chopra S, Safi B, Blixt M, Sandler S, Singh K. Assessing the effectiveness of Interleukin-2 therapy in experimental type 1 diabetes. Endocrine 2024; 85:626-637. [PMID: 38424350 PMCID: PMC11291609 DOI: 10.1007/s12020-024-03753-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 02/15/2024] [Indexed: 03/02/2024]
Abstract
AIM Much focus of immunotherapy for type 1 diabetes (T1D) has been devoted on selectively boosting regulatory T (Treg) cells using low dose IL-2 due to their constitutive expression of IL-2Rα, CD25. However, several clinical trials using a low dose of IL-2 only showed a limited improvement of metabolic control. It can therefore be hypothesized that further decreasing IL-2 dosage may increase the selective responsiveness of Treg cells. METHODS We induced experimental T1D using multiple low dose streptozotocin (STZ) injections and treated the mice with an ultra-low dose IL-2 (uIL-2, approximately 7-fold lower than low dose). Immune response was studied using multicolor flow cytometry. RESULTS We found that uIL-2 did not protect STZ mice from developing hyperglycemia. It did neither increase Treg cell proportions, nor did it correct the phenotypic shift of Treg cells seen in T1D. It only partially decreased the proportion of IFN-γ+ T cells. Likewise, uIL-2 also did not protect the dysfunction of regulatory B (Breg) cells. Strikingly, when administered in combination with an anti-inflammatory cytokine IL-35, uIL-2 abrogated IL-35's protective effect. Low dose IL-2, on the other hand, protected half of the STZ mice from developing hyperglycemia. No difference was found in the Treg and Breg response, and it only tended to decrease CD80 expression in macrophages and dendritic cells. CONCLUSION In conclusion, further decreasing IL-2 dosage may not be a suitable approach for T1D therapy, and the limited success suggests that an alternative low dose IL-2 therapy strategy or other immunotherapies should be considered.
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Affiliation(s)
- Zhengkang Luo
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
| | | | - Nour Hamze
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Elin Berggren
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Saloni Chopra
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Bilal Safi
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Martin Blixt
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Stellan Sandler
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Kailash Singh
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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Carbone F, Colamatteo A, La Rocca C, Lepore MT, Russo C, De Rosa G, Matarese A, Procaccini C, Matarese G. Metabolic Plasticity of Regulatory T Cells in Health and Autoimmunity. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1859-1866. [PMID: 38830147 DOI: 10.4049/jimmunol.2400079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/05/2024] [Indexed: 06/05/2024]
Abstract
Immunometabolism has been demonstrated to control immune tolerance and the pathogenic events leading to autoimmunity. Compelling experimental evidence also suggests that intracellular metabolic programs influence differentiation, phenotype, proliferation, and effector functions of anti-inflammatory CD4+CD25+Foxp3+ regulatory T (Treg) cells. Indeed, alterations in intracellular metabolism associate with quantitative and qualitative impairments of Treg cells in several pathological conditions. In this review, we summarize the most recent advances linking how metabolic pathways control Treg cell homeostasis and their alterations occurring in autoimmunity. Also, we analyze how metabolic manipulations could be employed to restore Treg cell frequency and function with the aim to create novel therapeutic opportunities to halt immune-mediated disorders.
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Grants
- 2022LNHZAP Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PE00000007 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PE00000006 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- RF-2019-12371111 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- PNRR-MAD-2022-12375634 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- GR-2018-12366154 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- 2022-PRsingle/013 Fondazione Italiana Sclerosi Multipla (FISM)
- P2022T4PKT Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- PNRR-MAD-2022-12376126 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- GR-2021-12373337 Italy Ministry of Health | Agenzia Italiana del Farmaco, Ministero della Salute (AIFA)
- 2022YMJXYT Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- P2022CMK43 Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
- 20225KH7BZ Ministero dell''''Istruzione, dell''''Università e della Ricerca (MIUR)
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Affiliation(s)
- Fortunata Carbone
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, Roma, Italy
| | - Alessandra Colamatteo
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Claudia La Rocca
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
| | - Maria Teresa Lepore
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
| | - Claudia Russo
- D.A.I. Medicina di Laboratorio e Trasfusionale, Azienda Ospedaliera Universitaria "Federico II," Napoli, Italy
| | - Giusy De Rosa
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Alessandro Matarese
- Dipartimento di Medicina Clinica e Chirurgia, Università degli Studi di Napoli "Federico II," Napoli, Italy
| | - Claudio Procaccini
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Unità di Neuroimmunologia, IRCCS-Fondazione Santa Lucia, Roma, Italy
| | - Giuseppe Matarese
- Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Napoli, Italy
- Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Napoli, Italy
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8
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Herold KC, Delong T, Perdigoto AL, Biru N, Brusko TM, Walker LSK. The immunology of type 1 diabetes. Nat Rev Immunol 2024; 24:435-451. [PMID: 38308004 PMCID: PMC7616056 DOI: 10.1038/s41577-023-00985-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2023] [Indexed: 02/04/2024]
Abstract
Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.
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Affiliation(s)
- Kevan C Herold
- Department of Immunobiology, Yale University, New Haven, CT, USA.
- Department of Internal Medicine, Yale University, New Haven, CT, USA.
| | - Thomas Delong
- Anschutz Medical Campus, University of Colorado, Denver, CO, USA
| | - Ana Luisa Perdigoto
- Department of Internal Medicine, Yale University, New Haven, CT, USA
- Internal Medicine, VA Connecticut Healthcare System, West Haven, CT, USA
| | - Noah Biru
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Lucy S K Walker
- Institute of Immunity & Transplantation, University College London, London, UK.
- Division of Infection & Immunity, University College London, London, UK.
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9
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Zhang R, Zhao Y, Chen X, Zhuang Z, Li X, Shen E. Low-dose IL-2 therapy in autoimmune diseases: An update review. Int Rev Immunol 2024; 43:113-137. [PMID: 37882232 DOI: 10.1080/08830185.2023.2274574] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 10/16/2023] [Indexed: 10/27/2023]
Abstract
Regulatory T (Treg) cells are essential for maintaining self-immune tolerance. Reduced numbers or functions of Treg cells have been involved in the pathogenesis of various autoimmune diseases and allograft rejection. Therefore, the approaches that increase the pool or suppressive function of Treg cells in vivo could be a general strategy to treat different autoimmune diseases and allograft rejection. Interleukin-2 (IL-2) is essential for the development, survival, maintenance, and function of Treg cells, constitutively expressing the high-affinity receptor of IL-2 and sensitive response to IL-2 in vivo. And low-dose IL-2 therapy in vivo could restore the imbalance between autoimmune response and self-tolerance toward self-tolerance via promoting Treg cell expansion and inhibiting follicular helper T (Tfh) and IL-17-producing helper T (Th17) cell differentiation. Currently, low-dose IL-2 treatment is receiving extensive attention in autoimmune disease and transplantation treatment. In this review, we summarize the biology of IL-2/IL-2 receptor, the mechanisms of low-dose IL-2 therapy in autoimmune diseases, the application in the progress of different autoimmune diseases, including Systemic Lupus Erythematosus (SLE), Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), Autoimmune Hepatitis (AIH), Alopecia Areata (AA), Immune Thrombocytopenia (ITP) and Chronic graft-versus-host-disease (GVHD). We also discuss the future directions to optimize low-dose IL-2 treatments.
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Affiliation(s)
- Ruizhi Zhang
- Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Yuyang Zhao
- Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
| | - Xiangming Chen
- Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
| | - Zhuoqing Zhuang
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Xiaomin Li
- Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Erxia Shen
- Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- The Second Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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10
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Joshi G, Das A, Verma G, Guchhait P. Viral infection and host immune response in diabetes. IUBMB Life 2024; 76:242-266. [PMID: 38063433 DOI: 10.1002/iub.2794] [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: 03/17/2023] [Accepted: 11/05/2023] [Indexed: 04/24/2024]
Abstract
Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.
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Affiliation(s)
- Garima Joshi
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Anushka Das
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Garima Verma
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
| | - Prasenjit Guchhait
- Regional Centre for Biotechnology, National Capital Region Biotech Science Cluster, Faridabad, India
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11
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Zhao L, Hu H, Zhang L, Liu Z, Huang Y, Liu Q, Jin L, Zhu M, Zhang L. Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2024; 5:e516. [PMID: 38617433 PMCID: PMC11014467 DOI: 10.1002/mco2.516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/16/2024] Open
Abstract
At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole-body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.
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Affiliation(s)
- Lu Zhao
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Haoran Hu
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Lin Zhang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Zheting Liu
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Yunchao Huang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Qian Liu
- National Demonstration Center for Experimental Traditional Chinese Medicines Education (Zhejiang Chinese Medical University)College of Pharmaceutical Science, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Liang Jin
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
- Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia MedicaShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Meifei Zhu
- Department of Critical Care MedicineThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)HangzhouChina
| | - Ling Zhang
- Department of Biology and MedicineCollege of Life Science, Zhejiang Chinese Medical UniversityHangzhouChina
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12
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Tuomela K, Levings MK. Genetic engineering of regulatory T cells for treatment of autoimmune disorders including type 1 diabetes. Diabetologia 2024; 67:611-622. [PMID: 38236408 DOI: 10.1007/s00125-023-06076-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 11/07/2023] [Indexed: 01/19/2024]
Abstract
Suppression of pathogenic immune responses is a major goal in the prevention and treatment of type 1 diabetes. Adoptive cell therapy using regulatory T cells (Tregs), a naturally suppressive immune subset that is often dysfunctional in type 1 diabetes, is a promising approach to achieving localised and specific immune suppression in the pancreas or site of islet transplant. However, clinical trials testing administration of polyclonal Tregs in recent-onset type 1 diabetes have observed limited efficacy despite an excellent safety profile. Several barriers to efficacy have been identified, including lack of antigen specificity, low cell persistence post-administration and difficulty in generating sufficient cell numbers. Fortunately, the emergence of advanced gene editing techniques has opened the door to new strategies to engineer Tregs with improved specificity and function. These strategies include the engineering of FOXP3 expression to produce a larger source of suppressive cells for infusion, expressing T cell receptors or chimeric antigen receptors to generate antigen-specific Tregs and improving Treg survival by targeting cytokine pathways. Although these approaches are being applied in a variety of autoimmune and transplant contexts, type 1 diabetes presents unique opportunities and challenges for the genetic engineering of Tregs for adoptive cell therapy. Here we discuss the role of Tregs in type 1 diabetes pathogenesis and the application of Treg engineering in the context of type 1 diabetes.
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Affiliation(s)
- Karoliina Tuomela
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Megan K Levings
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
- Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
- School of Biomedical Engineering, University of British Columbia, Vancouver, Canada.
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13
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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14
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Zhang J, Liu H, Chen Y, Liu H, Zhang S, Yin G, Xie Q. Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis. Front Immunol 2024; 15:1312919. [PMID: 38322264 PMCID: PMC10844451 DOI: 10.3389/fimmu.2024.1312919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune condition marked by inflammation of the joints, degradation of the articular cartilage, and bone resorption. Recent studies found the absolute and relative decreases in circulating regulatory T cells (Tregs) in RA patients. Tregs are a unique type of cells exhibiting immunosuppressive functions, known for expressing the Foxp3 gene. They are instrumental in maintaining immunological tolerance and preventing autoimmunity. Increasing the absolute number and/or enhancing the function of Tregs are effective strategies for treating RA. This article reviews the studies on the mechanisms and targeted therapies related to Tregs in RA, with a view to provide better ideas for the treatment of RA.
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Affiliation(s)
- Jiaqian Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuehong Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Huan Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Shengxiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Geng Yin
- Department of General Practice, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
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15
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Kawakami R, Sakaguchi S. Regulatory T Cells for Control of Autoimmunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1444:67-82. [PMID: 38467973 DOI: 10.1007/978-981-99-9781-7_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Regulatory T (Treg) cells, which specifically express the master transcription factor FoxP3, are indispensable for the maintenance of immunological self-tolerance and homeostasis. Their functional or numerical anomalies can be causative of autoimmune and other inflammatory diseases. Recent advances in the research of the cellular and molecular basis of how Treg cells develop, exert suppression, and maintain their function have enabled devising various ways for controlling physiological and pathological immune responses by targeting Treg cells. It is now envisaged that Treg cells as a "living drug" are able to achieve antigen-specific immune suppression of various immune responses and reestablish immunological self-tolerance in the clinic.
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Affiliation(s)
- Ryoji Kawakami
- Kyoto University, Kyoto, Japan
- Osaka University, Osaka, Japan
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16
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Thatte AS, Hamilton AG, Nachod BE, Mukalel AJ, Billingsley MM, Palanki R, Swingle KL, Mitchell MJ. mRNA Lipid Nanoparticles for Ex Vivo Engineering of Immunosuppressive T Cells for Autoimmunity Therapies. NANO LETTERS 2023; 23:10179-10188. [PMID: 37906000 DOI: 10.1021/acs.nanolett.3c02573] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Cell-based therapies for autoimmune diseases have gained significant traction, with several approaches centered around the regulatory T (Treg) cell─a well-known immunosuppressive cell characterized by its expression of the transcription factor Foxp3. Unfortunately, due to low numbers of Treg cells available in circulation, harvesting and culturing Treg cells remains a challenge. It has been reported that engineering Foxp3 expression in CD4+ T cells can result in a Treg-like phenotype; however, current methods result in the inefficient engineering of these cells. Here, we develop an ionizable lipid nanoparticle (LNP) platform to effectively deliver Foxp3 mRNA to CD4+ T cells. We successfully engineer CD4+ T cells into Foxp3-T (FP3T) cells that transiently exhibit an immunosuppressive phenotype and functionally suppress the proliferation of effector T cells. These results demonstrate the promise of an LNP platform for engineering immunosuppressive T cells with potential applications in autoimmunity therapies.
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Affiliation(s)
- Ajay S Thatte
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Alex G Hamilton
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Benjamin E Nachod
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Alvin J Mukalel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Margaret M Billingsley
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Rohan Palanki
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Kelsey L Swingle
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 United States
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
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17
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Kishimoto TK, Fournier M, Michaud A, Rizzo G, Roy C, Capela T, Nukolova N, Li N, Doyle L, Fu FN, VanDyke D, Traber PG, Spangler JB, Leung SS, Ilyinskii PO. Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease. J Autoimmun 2023; 140:103125. [PMID: 37844543 DOI: 10.1016/j.jaut.2023.103125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/26/2023] [Accepted: 10/04/2023] [Indexed: 10/18/2023]
Abstract
Interleukin-2 (IL-2) therapies targeting the high affinity IL-2 receptor expressed on regulatory T cells (Tregs) have shown promising therapeutic benefit in autoimmune diseases through nonselective expansion of pre-existing Treg populations, but are potentially limited by the inability to induce antigen-specific Tregs, as well as by dose-limiting activation of effector immune cells in settings of inflammation. We recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, which induce selective immune tolerance to co-administered antigens but do not increase total Treg numbers. Here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Tregs when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. Importantly, ImmTOR also increases the therapeutic window of engineered IL-2 molecules by mitigating effector immune cell expansion and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, IL-2 mutein shows potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.
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Affiliation(s)
| | | | | | - Gina Rizzo
- Selecta Biosciences, Watertown, MA, 02472, USA
| | | | | | | | - Ning Li
- Selecta Biosciences, Watertown, MA, 02472, USA
| | - Liam Doyle
- Selecta Biosciences, Watertown, MA, 02472, USA
| | - Fen-Ni Fu
- Selecta Biosciences, Watertown, MA, 02472, USA
| | - Derek VanDyke
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
| | | | - Jamie B Spangler
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA
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18
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Shapiro MR, Peters LD, Brown ME, Cabello-Kindelan C, Posgai AL, Bayer AL, Brusko TM. Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1108-1122. [PMID: 37594278 PMCID: PMC10511790 DOI: 10.4049/jimmunol.2200651] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 08/01/2023] [Indexed: 08/19/2023]
Abstract
IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1 receptor was elevated on murine memory and human naive Treg subsets. IL-2 and IGF1 promoted PI3K/Akt signaling in Tregs, inducing thymically-derived Treg expansion beyond either agent alone in NOD mice. Increased populations of murine Tregs of naive or memory, as well as CD5lo polyclonal or CD5hi likely self-reactive, status were also observed. Expansion was attributed to increased IL-2Rγ subunit expression on murine Tregs exposed to IL-2 and IGF1 as compared with IL-2 or IGF1 alone. Assessing translational capacity, incubation of naive human CD4+ T cells with IL-2 and IGF1 enhanced thymically-derived Treg proliferation in vitro, without the need for TCR ligation. We then demonstrated that IGF1 and IL-2 or IL-7, which is also IL-2Rγ-chain dependent, can be used to induce proliferation of genetically engineered naive human Tregs or T conventional cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive homeostatic T cell expansion, both in vitro and in vivo, for cellular therapeutics and ex vivo gene editing.
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Affiliation(s)
- Melanie R. Shapiro
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
| | - Leeana D. Peters
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
| | - Matthew E. Brown
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
| | | | - Amanda L. Posgai
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
| | - Allison L. Bayer
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL
| | - Todd M. Brusko
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
- Department of Pediatrics, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL
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19
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Krishnamurthy B, Lacorcia M, Kay TWH, Thomas HE, Mannering SI. Monitoring immunomodulation strategies in type 1 diabetes. Front Immunol 2023; 14:1206874. [PMID: 37346035 PMCID: PMC10279879 DOI: 10.3389/fimmu.2023.1206874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 05/26/2023] [Indexed: 06/23/2023] Open
Abstract
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease. Short-term treatment with agents targeting T cells, B cells and inflammatory cytokines to modify the disease course resulted in a short-term pause in disease activity. Lessons learnt from these trials will be discussed in this review. It is expected that effective disease-modifying agents will become available for use in earlier stages of T1D. Progress has been made to analyze antigen-specific T cells with standardization of T cell assay and discovery of antigen epitopes but there are many challenges. High-dimensional profiling of gene, protein and TCR expression at single cell level with innovative computational tools should lead to novel biomarker discovery. With this, assays to detect, quantify and characterize the phenotype and function of antigen-specific T cells will continuously evolve. An improved understanding of T cell responses will help researchers and clinicians to better predict disease onset, and progression, and the therapeutic efficacy of interventions to prevent or arrest T1D.
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Affiliation(s)
- Balasubramanian Krishnamurthy
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Matthew Lacorcia
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
| | - Thomas W. H. Kay
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Helen E. Thomas
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Stuart I. Mannering
- Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, Australia
- Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC, Australia
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20
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Huang M, Chen W, Wang M, Huang Y, Liu H, Ming Y, Chen Y, Tang Z, Jia B. Advanced Delivery Strategies for Immunotherapy in Type I Diabetes Mellitus. BioDrugs 2023; 37:331-352. [PMID: 37178431 PMCID: PMC10182560 DOI: 10.1007/s40259-023-00594-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2023] [Indexed: 05/15/2023]
Abstract
Type 1 diabetes mellitus (T1DM) has been defined as an autoimmune disease characterised by immune-mediated destruction of the pancreatic β cells, leading to absolute insulin deficiency and hyperglycaemia. Current research has increasingly focused on immunotherapy based on immunosuppression and regulation to rescue T-cell-mediated β-cell destruction. Although T1DM immunotherapeutic drugs are constantly under clinical and preclinical development, several key challenges remain, including low response rates and difficulty in maintaining therapeutic effects. Advanced drug delivery strategies can effectively harness immunotherapies and improve their potency while reducing their adverse effects. In this review, we briefly introduce the mechanisms of T1DM immunotherapy and focus on the current research status of the integration of the delivery techniques in T1DM immunotherapy. Furthermore, we critically analyse the challenges and future directions of T1DM immunotherapy.
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Affiliation(s)
- Mingshu Huang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Weixing Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Min Wang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yisheng Huang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Hongyu Liu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yue Ming
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Yuanxin Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Zhengming Tang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China
| | - Bo Jia
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, China.
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21
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Mancuso G, Bechi Genzano C, Fierabracci A, Fousteri G. Type 1 diabetes and inborn errors of immunity: Complete strangers or 2 sides of the same coin? J Allergy Clin Immunol 2023:S0091-6749(23)00427-X. [PMID: 37097271 DOI: 10.1016/j.jaci.2023.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/31/2023] [Accepted: 03/31/2023] [Indexed: 04/26/2023]
Abstract
Type 1 diabetes (T1D) is a polygenic disease and does not follow a mendelian pattern. Inborn errors of immunity (IEIs), on the other hand, are caused by damaging germline variants, suggesting that T1D and IEIs have nothing in common. Some IEIs, resulting from mutations in genes regulating regulatory T-cell homeostasis, are associated with elevated incidence of T1D. The genetic spectrum of IEIs is gradually being unraveled; consequently, molecular pathways underlying human monogenic autoimmunity are being identified. There is an appreciable overlap between some of these pathways and the genetic variants that determine T1D susceptibility, suggesting that after all, IEI and T1D are 2 sides of the same coin. The study of monogenic IEIs with a variable incidence of T1D has the potential to provide crucial insights into the mechanisms leading to T1D. These insights contribute to the definition of T1D endotypes and explain disease heterogeneity. In this review, we discuss the interconnected pathogenic pathways of autoimmunity, β-cell function, and primary immunodeficiency. We also examine the role of environmental factors in disease penetrance as well as the circumstantial evidence of IEI drugs in preventing and curing T1D in individuals with IEIs, suggesting the repositioning of these drugs also for T1D therapy.
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Affiliation(s)
- Gaia Mancuso
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Camillo Bechi Genzano
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | | | - Georgia Fousteri
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
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22
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Zala A, Thomas R. Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves' disease. Clin Exp Immunol 2023; 211:164-175. [PMID: 36545825 PMCID: PMC10019129 DOI: 10.1093/cei/uxac115] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 10/23/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Type 1 diabetes and Graves' disease are chronic autoimmune conditions, characterized by a dysregulated immune response. In Type 1 diabetes, there is beta cell destruction and subsequent insulin deficiency whereas in Graves' disease, there is unregulated excessive thyroid hormone production. Both diseases result in significant psychosocial, physiological, and emotional burden. There are associated risks of diabetic ketoacidosis and hypoglycaemia in Type 1 diabetes and risks of thyrotoxicosis and orbitopathy in Graves' disease. Advances in the understanding of the immunopathogenesis and response to immunotherapy in Type 1 diabetes and Graves' disease have facilitated the introduction of targeted therapies to induce self-tolerance, and subsequently, the potential to induce long-term remission if effective. We explore current research surrounding the use of antigen-specific immunotherapies, with a focus on human studies, in Type 1 diabetes and Graves' disease including protein-based, peptide-based, dendritic-cell-based, and nanoparticle-based immunotherapies, including discussion of factors to be considered when translating immunotherapies to clinical practice.
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Affiliation(s)
- Aakansha Zala
- Frazer Institute, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Ranjeny Thomas
- Correspondence: Ranjeny Thomas, Frazer Institute, The University of Queensland.
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23
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Harris F, Berdugo YA, Tree T. IL-2-based approaches to Treg enhancement. Clin Exp Immunol 2023; 211:149-163. [PMID: 36399073 PMCID: PMC10019135 DOI: 10.1093/cei/uxac105] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/12/2022] [Accepted: 11/17/2022] [Indexed: 11/19/2022] Open
Abstract
Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
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Affiliation(s)
- Ffion Harris
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Yoana Arroyo Berdugo
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Timothy Tree
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
- National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
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24
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Nickle RA, DeOca KB, Garcia BL, Mannie MD. Soluble CD25 imposes a low-zone IL-2 signaling environment that favors competitive outgrowth of antigen-experienced CD25 high regulatory and memory T cells. Cell Immunol 2023; 384:104664. [PMID: 36642016 PMCID: PMC10257407 DOI: 10.1016/j.cellimm.2023.104664] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/13/2022] [Accepted: 01/03/2023] [Indexed: 01/07/2023]
Abstract
This study focused on soluble (s)CD25-mediated regulation of IL-2 signaling in murine and human CD4+ T cells. Recombinant sCD25 reversibly sequestered IL-2 to limit acute maximal proliferative responses while preserving IL-2 bioavailability to subsequently maintain low-zone IL-2 signaling during prolonged culture. By inhibiting IL-2 signaling during acute activation, sCD25 suppressed T-cell growth and inhibited IL-2-evoked transmembrane CD25 expression, thereby resulting in lower prevalence of CD25high T cells. By inhibiting IL-2 signaling during quiescent IL-2-mediated growth, sCD25 competed with transmembrane CD25, IL2Rβγ, and IL2Rαβγ receptors for limited pools of IL-2 such that sCD25 exhibited strong or weak inhibitory efficacy in IL-2-stimulated cultures of CD25low or CD25high T cells, respectively. Preferential blocking of IL-2 signaling in CD25low but not CD25high T cells caused competitive enrichment of CD25high memory/effector and regulatory FOXP3+ subsets. In conclusion, sCD25 modulates IL-2 bioavailability to limit CD25 expression during acute activation while enhancing CD25highT-cell dominance during low-zone homeostatic IL-2-mediated expansion, thereby 'flattening' the inflammatory curve over time.
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Affiliation(s)
- Rebecca A Nickle
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Kayla B DeOca
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Brandon L Garcia
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Mark D Mannie
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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25
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Klatka M, Rysz I, Hymos A, Polak A, Mertowska P, Mertowski S, Smolak K, Grywalska E. Effect of Epstein-Barr Virus Infection on Selected Immunological Parameters in Children with Type 1 Diabetes. Int J Mol Sci 2023; 24:ijms24032392. [PMID: 36768715 PMCID: PMC9917181 DOI: 10.3390/ijms24032392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Diabetes mellitus is a group of metabolic disorders with different etiologies, pathogeneses and clinical pictures, characterized by chronic hyperglycemia due to abnormal insulin secretion or action. Type 1 diabetes mellitus is the most common type of diabetes mellitus in children and adolescents, accounting for about 90% of diabetes in the population under the age of 18. The etiopathogenesis of type 1 diabetes is multifactorial. The disease occurs as a result of the interaction of three factors: genetic predisposition, environmental factors and the immune response. Research in recent years has focused on the involvement of Epstein-Barr virus (EBV) in the pathogenesis of type I diabetes. The goals of treating type 1 diabetes include maintaining blood-glucose, fructosamine and glycated hemoglobin (HbA1c) levels; therefore, the main purpose of this study was to evaluate the effect of EBV infection on the activation of selected immune cells, fructosamine levels and HbA1c levels in children with type I diabetes. Based on our study, we found a lower percentage of CD8+ T lymphocytes with expression of the CD69 molecule in patients with anti-VCA antibodies in the IgG class, and a lower percentage of CD8+ T lymphocytes with expression of the CD25+ molecule in patients with anti-EBNA-1 antibodies in the IgG class, which may indicate limited control of the immune system during EBV infection in patients. There was a lower percentage of CD3+CD4+ T lymphocytes secreting IL-4 in the study group, indicating that a deficiency in IL-4 production may be related to the development of type 1 diabetes. There was an increase in the percentage of CD4+CD3+IL-10 lymphocytes in the study group with anti-VCA antibodies present in the IgG class and anti-EBNA-1 antibodies in the IgG class compared to the patients without antibodies. In addition, there was a significant increase in fructosamine levels and higher glycated hemoglobin levels in the study group with antibodies to EBV antigens. In addition, an increase in the percentage of T lymphocytes with a CD4+CD3+IL-17+ phenotype in the patients with anti-VCA IgG antibodies was confirmed, and higher HbA1c levels may suggest that EBV infection is accompanied by an increase in IL-17 secretion.
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Affiliation(s)
- Maria Klatka
- Department of Pediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Izabela Rysz
- Department of Pediatric Endocrinology and Diabetology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Anna Hymos
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Agnieszka Polak
- Department of Endocrinology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Paulina Mertowska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence: (P.M.); (S.M.)
| | - Sebastian Mertowski
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence: (P.M.); (S.M.)
| | - Konrad Smolak
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland
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26
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Bluestone JA, McKenzie BS, Beilke J, Ramsdell F. Opportunities for Treg cell therapy for the treatment of human disease. Front Immunol 2023; 14:1166135. [PMID: 37153574 PMCID: PMC10154599 DOI: 10.3389/fimmu.2023.1166135] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/22/2023] [Indexed: 05/09/2023] Open
Abstract
Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammatory diseases. This small CD4+ T cell population can develop in the thymus and in the peripheral tissues of the immune system through the expression of an epigenetically stabilized transcription factor, FOXP3. Treg cells mediate their tolerogenic effects using multiple modes of action, including the production of inhibitory cytokines, cytokine starvation of T effector (e.g., IL-2), Teff suppression by metabolic disruption, and modulation of antigen-presenting cell maturation or function. These activities together result in the broad control of various immune cell subsets, leading to the suppression of cell activation/expansion and effector functions. Moreover, these cells can facilitate tissue repair to complement their suppressive effects. In recent years, there has been an effort to harness Treg cells as a new therapeutic approach to treat autoimmune and other immunological diseases and, importantly, to re-establish tolerance. Recent synthetic biological advances have enabled the cells to be genetically engineered to achieve tolerance and antigen-specific immune suppression by increasing their specific activity, stability, and efficacy. These cells are now being tested in clinical trials. In this review, we highlight both the advances and the challenges in this arena, focusing on the efforts to develop this new pillar of medicine to treat and cure a variety of diseases.
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27
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Wan S, Xu W, Xie B, Guan C, Song X. The potential of regulatory T cell-based therapies for alopecia areata. Front Immunol 2023; 14:1111547. [PMID: 37205097 PMCID: PMC10186346 DOI: 10.3389/fimmu.2023.1111547] [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: 11/29/2022] [Accepted: 04/07/2023] [Indexed: 05/21/2023] Open
Abstract
Cytotoxic T lymphocyte has been a concern for the etiopathogenesis of alopecia areata (AA), some recent evidence suggests that the regulatory T (Treg) cell deficiency is also a contributing factor. In the lesional scalp of AA, Treg cells residing in the follicles are impaired, leading to dysregulated local immunity and hair follicle (HF) regeneration disorders. New strategies are emerging to modulate Treg cells' number and function for autoimmune diseases. There is much interest to boost Treg cells in AA patients to suppress the abnormal autoimmunity of HF and stimulate hair regeneration. With few satisfactory therapeutic regimens available for AA, Treg cell-based therapies could be the way forward. Specifically, CAR-Treg cells and novel formulations of low-dose IL-2 are the alternatives.
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Affiliation(s)
- Sheng Wan
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wen Xu
- School of Medicine, Zhejiang University, Yuhangtang, Hangzhou, China
| | - Bo Xie
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cuiping Guan
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiuzu Song, ; Cuiping Guan,
| | - Xiuzu Song
- Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiuzu Song, ; Cuiping Guan,
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28
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Mooslechner AA, Schuller M, Artinger K, Kirsch AH, Schabhüttl C, Eller P, Rosenkranz AR, Eller K. Low-Dose rIL-15 Protects from Nephrotoxic Serum Nephritis via CD8 + T Cells. Cells 2022; 11:cells11223656. [PMID: 36429085 PMCID: PMC9688325 DOI: 10.3390/cells11223656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/14/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Rapid progressive glomerulonephritis (GN) often leads to end-stage kidney disease, driving the need for renal replacement therapy and posing a global health burden. Low-dose cytokine-based immunotherapies provide a new strategy to treat GN. IL-15 is a strong candidate for the therapy of immune-mediated kidney disease since it has proven to be tubular-protective before. Therefore, we set out to test the potential of low-dose rIL-15 treatment in a mouse model of nephrotoxic serum nephritis (NTS), mimicking immune complex-driven GN in humans. A single low-dose treatment with rIL-15 ameliorated NTS, reflected by reduced albuminuria, less tissue scarring, fewer myeloid cells in the kidney, and improved tubular epithelial cell survival. In addition, CD8+ T cells, a primary target of IL-15, showed altered gene expression and function corresponding with less cytotoxicity mediated by rIL-15. With the use of transgenic knock-out mice, antibody depletion, and adoptive cell transfer studies, we here show that the beneficial effects of rIL-15 treatment in NTS depended on CD8+ T cells, suggesting a pivotal role for them in the underlying mechanism. Our findings add to existing evidence of the association of IL-15 with kidney health and imply a potential for low-dose rIL-15 immunotherapies in GN.
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Affiliation(s)
- Agnes A. Mooslechner
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Max Schuller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Katharina Artinger
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Alexander H. Kirsch
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Corinna Schabhüttl
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Philipp Eller
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Alexander R. Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
- Correspondence:
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29
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Wang CJ, Petersone L, Edner NM, Heuts F, Ovcinnikovs V, Ntavli E, Kogimtzis A, Fabri A, Elfaki Y, Houghton LP, Hosse RJ, Schubert DA, Frei AP, Ross EM, Walker LSK. Costimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity. Nat Commun 2022; 13:6757. [PMID: 36347877 PMCID: PMC9643453 DOI: 10.1038/s41467-022-34477-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 10/26/2022] [Indexed: 11/11/2022] Open
Abstract
Blockade of CD28 costimulation with CTLA-4-Ig/Abatacept is used to dampen effector T cell responses in autoimmune and transplantation settings. However, a significant drawback of this approach is impaired regulatory T cell homeostasis that requires CD28 signaling. Therefore, strategies that restrict the effects of costimulation blockade to effector T cells would be advantageous. Here we probe the relative roles of CD28 and IL-2 in maintaining Treg. We find provision of IL-2 counteracts the regulatory T cell loss induced by costimulation blockade while minimally affecting the conventional T cell compartment. These data suggest that combining costimulation blockade with IL-2 treatment may selectively impair effector T cell responses while maintaining regulatory T cells. Using a mouse model of autoimmune diabetes, we show combined therapy supports regulatory T cell homeostasis and protects from disease. These findings are recapitulated in humanised mice using clinically relevant reagents and provide an exemplar for rational use of a second immunotherapy to offset known limitations of the first.
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Affiliation(s)
- Chun Jing Wang
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Lina Petersone
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Natalie M Edner
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Frank Heuts
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Vitalijs Ovcinnikovs
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Elisavet Ntavli
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Alexandros Kogimtzis
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Astrid Fabri
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Yassin Elfaki
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Luke P Houghton
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Ralf J Hosse
- Roche Innovation Center Zurich, Roche Pharma Research & Early Development (pRED), Schlieren, Switzerland
| | - David A Schubert
- Roche Innovation Center Basel, Roche Pharma Research & Early Development (pRED), Basel, Switzerland
| | - Andreas P Frei
- Roche Innovation Center Basel, Roche Pharma Research & Early Development (pRED), Basel, Switzerland
| | - Ellen M Ross
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK
| | - Lucy S K Walker
- Institute of Immunity & Transplantation, Pears Building, University College London Division of Infection & Immunity, London, UK.
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30
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Du C, Whiddett RO, Buckle I, Chen C, Forbes JM, Fotheringham AK. Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development. Cells 2022; 11:3503. [PMID: 36359899 PMCID: PMC9657002 DOI: 10.3390/cells11213503] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 08/08/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host's immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host-pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.
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Affiliation(s)
- Chenping Du
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Rani O. Whiddett
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
| | - Irina Buckle
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Chen Chen
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Josephine M. Forbes
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg 3084, Australia
| | - Amelia K. Fotheringham
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
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31
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Anderson RL, DiMeglio LA, Mander AP, Dayan CM, Linsley PS, Herold KC, Marinac M, Ahmed ST. Innovative Designs and Logistical Considerations for Expedited Clinical Development of Combination Disease-Modifying Treatments for Type 1 Diabetes. Diabetes Care 2022; 45:2189-2201. [PMID: 36150059 PMCID: PMC9911317 DOI: 10.2337/dc22-0308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023]
Abstract
It has been 100 years since the life-saving discovery of insulin, yet daily management of type 1 diabetes (T1D) remains challenging. Even with closed-loop systems, the prevailing need for persons with T1D to attempt to match the kinetics of insulin activity with the kinetics of carbohydrate metabolism, alongside dynamic life factors affecting insulin requirements, results in the need for frequent interventions to adjust insulin dosages or consume carbohydrates to correct mismatches. Moreover, peripheral insulin dosing leaves the liver underinsulinized and hyperglucagonemic and peripheral tissues overinsulinized relative to their normal physiologic roles in glucose homeostasis. Disease-modifying therapies (DMT) to preserve and/or restore functional β-cell mass with controlled or corrected autoimmunity would simplify exogenous insulin need, thereby reducing disease mortality, morbidity, and management burdens. However, identifying effective DMTs for T1D has proven complex. There is some consensus that combination DMTs are needed for more meaningful clinical benefit. Other complexities are addressable with more innovative trial designs and logistics. While no DMT has yet been approved for marketing, existing regulatory guidance provides opportunities to further "de-risk" development. The T1D development ecosystem can accelerate progress by using more innovative ways for testing DMTs for T1D. This perspective outlines suggestions for accelerating evaluation of candidate T1D DMTs, including combination therapies, by use of innovative trial designs, enhanced logistical coordination of efforts, and regulatory guidance for expedited development, combination therapies, and adaptive designs.
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Affiliation(s)
| | - Linda A. DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Adrian P. Mander
- Centre for Trials Research, Cardiff University School of Medicine, Cardiff, U.K
| | - Colin M. Dayan
- Centre for Endocrine and Diabetes Science, Cardiff University School of Medicine, Cardiff, U.K
| | - Peter S. Linsley
- Systems Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Kevan C. Herold
- Departments of Immunobiology and Internal Medicine, Yale University, New Haven, CT
| | | | - Simi T. Ahmed
- New York Stem Cell Foundation Research Institute, New York, NY
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32
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Gonzalez-Alcocer A, Gopar-Cuevas Y, Soto-Dominguez A, Loera-Arias MDJ, Saucedo-Cardenas O, Montes de Oca-Luna R, Rodriguez-Rocha H, Garcia-Garcia A. Peripheral tissular analysis of rapamycin's effect as a neuroprotective agent in vivo. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1239-1255. [PMID: 35895156 DOI: 10.1007/s00210-022-02276-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/15/2022] [Indexed: 10/16/2022]
Abstract
Rapamycin is the best-characterized autophagy inducer, which is related to its antiaging and neuroprotective effects. Although rapamycin is an FDA-approved drug for human use in organ transplantation and cancer therapy, its administration as an antiaging and neuroprotective agent is still controversial because of its immunosuppressive and reported side effects. Therefore, it is critical to determine whether the dose that exerts a neuroprotective effect, 35 times lower than that used as an immunosuppressant agent, harms peripheral organs. We validated the rapamycin neuroprotective dosage in a Parkinson's disease (PD) model induced with paraquat. C57BL/6 J mice were treated with intraperitoneal (IP) rapamycin (1 mg/kg) three times per week, followed by paraquat (10 mg/kg) twice per week for 6 weeks, along with rapamycin on alternate days. Rapamycin significantly decreased dopaminergic neuronal loss induced by paraquat. Since rapamycin's neuroprotective effect in a PD model was observed at 7 weeks of treatment; we evaluated its effect on the liver, kidney, pancreas, and spleen. In addition, we prolonged treatment with rapamycin for 14 weeks. Tissue sections were subjected to histochemical, immunodetection, and morphometric analysis. Chronic rapamycin administration does not affect bodyweight, survival, and liver or kidney morphology. Although the pancreas tissular architecture and cellular distribution in Langerhans islets are modified, they may be reversible. The spleen B lymphocyte and macrophage populations were decreased. Notably, the lymphocyte T population was not affected. Therefore, chronic administration of a rapamycin neuroprotective dose does not produce significant tissular alterations. Our findings support the therapeutic potential of rapamycin as a neuroprotective agent.
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Affiliation(s)
- Alfredo Gonzalez-Alcocer
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Yareth Gopar-Cuevas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Adolfo Soto-Dominguez
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Maria de Jesus Loera-Arias
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Odila Saucedo-Cardenas
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Roberto Montes de Oca-Luna
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Humberto Rodriguez-Rocha
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México
| | - Aracely Garcia-Garcia
- Departamento de Histología, Facultad de Medicina, Universidad Autónoma de Nuevo León, Francisco I. Madero S/N, 64460, Monterrey, Nuevo León, México.
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33
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Nepom GT. Synergistic targeting of immunologic pathways to empower durable tolerance therapies. Front Immunol 2022; 13:962177. [PMID: 36119087 PMCID: PMC9478166 DOI: 10.3389/fimmu.2022.962177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Gerald T. Nepom
- Immune Tolerance Network and Benaroya Research Institute, Seattle, WA, United States
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34
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Tizaoui K, Shin JI, Jeong GH, Yang JW, Park S, Kim JH, Hwang SY, Park SJ, Koyanagi A, Smith L. Genetic Polymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina (B Aires) 2022; 58:medicina58081034. [PMID: 36013501 PMCID: PMC9415475 DOI: 10.3390/medicina58081034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
It is known that the etiology and clinical outcomes of autoimmune diseases are associated with a combination of genetic and environmental factors. In the case of the genetic factor, the SNPs of the PTPN22 gene have shown strong associations with several diseases. The recent exploding numbers of genetic studies have made it possible to find these associations rapidly, and a variety of autoimmune diseases were found to be associated with PTPN22 polymorphisms. Proteins encoded by PTPN22 play a key role in the adaptative and immune systems by regulating both T and B cells. Gene variants, particularly SNPs, have been shown to significantly disrupt several immune functions. In this review, we summarize the mechanism of how PTPN22 and its genetic variants are involved in the pathophysiology of autoimmune diseases. In addition, we sum up the findings of studies reporting the genetic association of PTPN22 with different types of diseases, including type 1 diabetes mellitus, systemic lupus erythematosus, juvenile idiopathic arthritis, and several other diseases. By understanding these findings comprehensively, we can explain the complex etiology of autoimmunity and help to determine the criteria of disease diagnosis and prognosis, as well as medication developments.
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Affiliation(s)
- Kalthoum Tizaoui
- Department of Basic Sciences, Division of Histology and Immunology, Faculty of Medicine Tunis, Tunis El Manar University, Tunis 2092, Tunisia;
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Gwang Hun Jeong
- College of Medicine, Gyeongsang National University, Jinju 52727, Korea;
| | - Jae Won Yang
- Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Seoyeon Park
- Yonsei University College of Medicine, Seoul 06273, Korea; (S.P.); (S.Y.H.)
| | - Ji Hong Kim
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Korea;
- Correspondence: ; Tel.: +82-2-2019-3352; Fax: +82-2-3461-9473
| | - Soo Young Hwang
- Yonsei University College of Medicine, Seoul 06273, Korea; (S.P.); (S.Y.H.)
| | - Se Jin Park
- Department of Pediatrics, Eulji University School of Medicine, Daejeon 35233, Korea;
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, CIBERSAM, Dr. Antoni Pujadas, 42, Sant Boi de Llobregat, 08830 Barcelona, Spain;
- ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
| | - Lee Smith
- Centre for Health Performance and Wellbeing, Anglia Ruskin University, Cambridge CB1 1PT, UK;
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Scherm MG, Wyatt RC, Serr I, Anz D, Richardson SJ, Daniel C. Beta cell and immune cell interactions in autoimmune type 1 diabetes: How they meet and talk to each other. Mol Metab 2022; 64:101565. [PMID: 35944899 PMCID: PMC9418549 DOI: 10.1016/j.molmet.2022.101565] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/08/2022] [Accepted: 07/27/2022] [Indexed: 10/31/2022] Open
Abstract
Background Scope of review Major conclusions
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Personalized Immunotherapies for Type 1 Diabetes: Who, What, When, and How? J Pers Med 2022; 12:jpm12040542. [PMID: 35455658 PMCID: PMC9031881 DOI: 10.3390/jpm12040542] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 02/06/2023] Open
Abstract
Our understanding of the immunopathological features of type 1 diabetes (T1D) has greatly improved over the past two decades and has shed light on disease heterogeneity dictated by multiple immune, metabolic, and clinical parameters. This may explain the limited effects of immunotherapies tested so far to durably revert or prevent T1D, for which life-long insulin replacement remains the only therapeutic option. In the era of omics and precision medicine, offering personalized treatment could contribute to turning this tide. Here, we discuss how to structure the selection of the right patient at the right time for the right treatment. This individualized therapeutic approach involves enrolling patients at a defined disease stage depending on the target and mode of action of the selected drug, and better stratifying patients based on their T1D endotype, reflecting intrinsic disease aggressiveness and immune context. To this end, biomarker screening will be critical, not only to help stratify patients and disease stage, but also to select the best predicted responders ahead of treatment and at early time points during clinical trials. This strategy could contribute to increase therapeutic efficacy, notably through the selection of drugs with complementary effects, and to further develop precision multi-hit medicine.
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37
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Mitchell AM, Michels AW. Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes. Int J Mol Sci 2022; 23:3155. [PMID: 35328581 PMCID: PMC8954990 DOI: 10.3390/ijms23063155] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/03/2022] [Accepted: 03/12/2022] [Indexed: 12/15/2022] Open
Abstract
While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T cells in the destruction of pancreatic islets is well characterized, but immune-mediated mechanisms that contribute to T1D protection have not been fully elucidated. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules. In this review, we summarize what is known about the antigenic self-peptides recognized by Tregs in the context of T1D.
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Affiliation(s)
| | - Aaron W. Michels
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO 80045, USA;
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Lee J, Kim D, Min B. Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease. Front Immunol 2022; 13:865593. [PMID: 35359918 PMCID: PMC8963273 DOI: 10.3389/fimmu.2022.865593] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 02/22/2022] [Indexed: 01/04/2023] Open
Abstract
Foxp3+ regulatory T (Treg) cells are a CD4 T cell subset with unique immune regulatory function that are indispensable in immunity and tolerance. Their indisputable importance has been investigated in numerous disease settings and experimental models. Despite the extensive efforts in determining the cellular and molecular mechanisms operating their functions, our understanding their biology especially in vivo remains limited. There is emerging evidence that Treg cells resident in the non-lymphoid tissues play a central role in regulating tissue homeostasis, inflammation, and repair. Furthermore, tissue-specific properties of those Treg cells that allow them to express tissue specific functions have been explored. In this review, we will discuss the potential mechanisms and key cellular/molecular factors responsible for the homeostasis and functions of tissue resident Treg cells under steady-state and inflammatory conditions.
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Affiliation(s)
- Juyeun Lee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Dongkyun Kim
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Booki Min
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
- *Correspondence: Booki Min,
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Yang JHM, Ward-Hartstonge KA, Perry DJ, Blanchfield JL, Posgai AL, Wiedeman AE, Diggins K, Rahman A, Tree TIM, Brusko TM, Levings MK, James EA, Kent SC, Speake C, Homann D, Long SA. Guidelines for standardizing T-cell cytometry assays to link biomarkers, mechanisms, and disease outcomes in type 1 diabetes. Eur J Immunol 2022; 52:372-388. [PMID: 35025103 PMCID: PMC9006584 DOI: 10.1002/eji.202049067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 11/10/2021] [Accepted: 12/22/2021] [Indexed: 11/11/2022]
Abstract
Cytometric immunophenotyping is a powerful tool to discover and implement T-cell biomarkers of type 1 diabetes (T1D) progression and response to clinical therapy. Although many discovery-based T-cell biomarkers have been described, to date, no such markers have been widely adopted in standard practice. The heterogeneous nature of T1D and lack of standardized assays and experimental design across studies is a major barrier to the broader adoption of T-cell immunophenotyping assays. There is an unmet need to harmonize the design of immunophenotyping assays, including those that measure antigen-agnostic cell populations, such that data collected from different clinical trial sites and T1D cohorts are comparable, yet account for cohort-specific features and different drug mechanisms of action. In these Guidelines, we aim to provide expert advice on how to unify aspects of study design and practice. We provide recommendations for defining cohorts, method implementation, as well as tools for data analysis and reporting by highlighting and building on selected successes. Harmonization of cytometry-based T-cell assays will allow researchers to better integrate findings across trials, ultimately enabling the identification and validation of biomarkers of disease progression and treatment response in T1D.
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Affiliation(s)
- Jennie H. M. Yang
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College, London, UK
- National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
| | - Kirsten A. Ward-Hartstonge
- Department of Surgery, University of British Columbia, Vancouver, California, USA
- BC Children’s Hospital Research Institute, Vancouver, California, USA
| | - Daniel J. Perry
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - J. Lori Blanchfield
- Center for Translational Research, Benaroya Research Institute, Seattle, Washington, USA
| | - Amanda L. Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Alice E. Wiedeman
- Center for Translational Research, Benaroya Research Institute, Seattle, Washington, USA
| | - Kirsten Diggins
- Center for Translational Research, Benaroya Research Institute, Seattle, Washington, USA
| | - Adeeb Rahman
- Human Immune Monitoring Center, Hess Center for Science and Medicine, Icahn School of Medicine, New York, New York, USA
| | - Timothy I. M. Tree
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King’s College, London, UK
- National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
| | - Todd M. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Megan K. Levings
- Department of Surgery, University of British Columbia, Vancouver, California, USA
- BC Children’s Hospital Research Institute, Vancouver, California, USA
- School of Biomedical Engineering, University of British Columbia, California, USA
| | - Eddie A. James
- Center for Translational Research, Benaroya Research Institute, Seattle, Washington, USA
| | - Sally C. Kent
- Diabetes Center of Excellence, University of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Cate Speake
- Center for Interventional Immunology, Benaroya Research Institute, Seattle, Washington, USA
| | - Dirk Homann
- Precision Immunology Institute, Icahn School of Medicine, New York, New York, USA
- Diabetes, Obesity, & Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - S. Alice Long
- Center for Translational Research, Benaroya Research Institute, Seattle, Washington, USA
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Zhang M, Zhou Y, Xie Z, Luo S, Zhou Z, Huang J, Zhao B. New Developments in T Cell Immunometabolism and Therapeutic Implications for Type 1 Diabetes. Front Endocrinol (Lausanne) 2022; 13:914136. [PMID: 35757405 PMCID: PMC9226440 DOI: 10.3389/fendo.2022.914136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/09/2022] [Indexed: 11/23/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells and is becoming a serious public health threat. Despite the increasing incidence rate of T1D worldwide, our understanding of why T1D develops and how T cells lose their self-tolerance in this process remain limited. Recent advances in immunometabolism have shown that cellular metabolism plays a fundamental role in shaping T cell responses. T cell activation and proliferation are supported by metabolic reprogramming to meet the increased energy and biomass demand, and deregulation in immune metabolism can lead to autoimmune disorders. Specific metabolic pathways and factors have been investigated to rectify known deficiencies in several autoimmune diseases, including T1D. Most therapeutic strategies have concentrated on aerobic glycolysis to limit T cell responses, whereas glycolysis is the main metabolic pathway for T cell activation and proliferation. The use of metabolic inhibitors, especially glycolysis inhibitors may largely leave T cell function intact but primarily target those autoreactive T cells with hyperactivated metabolism. In this review, we provide an overview of metabolic reprogramming used by T cells, summarize the recent findings of key metabolic pathways and regulators modulating T cell homeostasis, differentiation, and function in the context of T1D, and discuss the opportunities for metabolic intervention to be employed to suppress autoreactive T cells and limit the progression of β-cell destruction.
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Affiliation(s)
- Mengdi Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yanyan Zhou
- Department of Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jiaqi Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Bin Zhao, ; ; Jiaqi Huang, ;
| | - Bin Zhao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- *Correspondence: Bin Zhao, ; ; Jiaqi Huang, ;
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Rickert CG, Markmann JF. Transplantation in the Age of Precision Medicine: The Emerging Field of Treg Therapy. Semin Nephrol 2022; 42:76-85. [DOI: 10.1016/j.semnephrol.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Oh E, McCown EM, Ahn M, Garcia PA, Branciamore S, Tang S, Zeng DF, Roep BO, Thurmond DC. Syntaxin 4 Enrichment in β-Cells Prevents Conversion to Autoimmune Diabetes in Non-Obese Diabetic (NOD) Mice. Diabetes 2021; 70:2837-2849. [PMID: 34556496 PMCID: PMC8660989 DOI: 10.2337/db21-0170] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 09/07/2021] [Indexed: 11/13/2022]
Abstract
Syntaxin 4 (STX4), a plasma membrane-localized SNARE protein, regulates human islet β-cell insulin secretion and preservation of β-cell mass. We found that human type 1 diabetes (T1D) and NOD mouse islets show reduced β-cell STX4 expression, consistent with decreased STX4 expression, as a potential driver of T1D phenotypes. To test this hypothesis, we generated inducible β-cell-specific STX4-expressing NOD mice (NOD-iβSTX4). Of NOD-iβSTX4 mice, 73% had sustained normoglycemia vs. <20% of control NOD (NOD-Ctrl) mice by 25 weeks of age. At 12 weeks of age, before diabetes conversion, NOD-iβSTX4 mice demonstrated superior whole-body glucose tolerance and β-cell glucose responsiveness than NOD-Ctrl mice. Higher β-cell mass and reduced β-cell apoptosis were also detected in NOD-iβSTX4 pancreata compared with pancreata of NOD-Ctrl mice. Single-cell RNA sequencing revealed that islets from NOD-iβSTX4 had markedly reduced interferon-γ signaling and tumor necrosis factor-α signaling via nuclear factor-κB in islet β-cells, including reduced expression of the chemokine CCL5; CD4+ regulatory T cells were also enriched in NOD-iβSTX4 islets. These results provide a deeper mechanistic understanding of STX4 function in β-cell protection and warrant further investigation of STX4 enrichment as a strategy to reverse or prevent T1D in humans or protect β-cell grafts.
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Affiliation(s)
- Eunjin Oh
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Erika M McCown
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Miwon Ahn
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Pablo A Garcia
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Sergio Branciamore
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Shanshan Tang
- Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - De-Fu Zeng
- Department of Immunology and Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Bart O Roep
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
| | - Debbie C Thurmond
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, Duarte, CA
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Vallianou NG, Stratigou T, Geladari E, Tessier CM, Mantzoros CS, Dalamaga M. Diabetes type 1: Can it be treated as an autoimmune disorder? Rev Endocr Metab Disord 2021; 22:859-876. [PMID: 33730229 DOI: 10.1007/s11154-021-09642-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Type 1 Diabetes Mellitus (T1DM) is characterized by progressive autoimmune-mediated destruction of the pancreatic beta-cells leading to insulin deficiency and hyperglycemia. It is associated with significant treatment burden and necessitates life-long insulin therapy. The role of immunotherapy in the prevention and management of T1DM is an evolving area of interest which has the potential to alter the natural history of this disease.In this review, we give insight into recent clinical trials related to the use of immunotherapeutic approaches for T1DM, such as proinflammatory cytokine inhibition, cell-depletion and cell-therapy approaches, autoantigen-specific treatments and stem cell therapies. We highlight the timing of intervention, aspects of therapy including adverse effects and the emergence of a novel lymphocyte crucial in T1DM autoimmunity. We also discuss the role of cardiac autoimmunity and its link to excess CVD risk in T1DM.We conclude that significant advances have been made in development of immunotherapeutic targets and agents for the treatment and prevention of T1DM. These immune-based therapies promise preservation of beta-cells and decreasing insulin dependency. In their current state, immunotherapeutic approaches cannot yet halt the progression from a preclinical state to overt T1DM nor can they replace standard insulin therapy in existing T1DM. It remains to be seen whether immunotherapy will ultimately play a key role in the prevention of progression to overt T1DM and whether it may find a place in our therapeutic armamentarium to improve clinical outcomes and quality of life in established T1DM.
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Affiliation(s)
- Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Theodora Stratigou
- Department of Endocrinology, Diabetes and Metabolic Diseases, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Goudi, Greece
| | - Eleni Geladari
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Christopher M Tessier
- Endocrinology Section, VA Boston Healthcare System, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA.
| | - Christos S Mantzoros
- Endocrinology Section, VA Boston Healthcare System, 1400 VFW Parkway West Roxbury, Boston, MA, 02132, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias, 11527, Athens, Goudi, Greece
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Conlon K, Watson DC, Waldmann TA, Valentin A, Bergamaschi C, Felber BK, Peer CJ, Figg WD, Potter EL, Roederer M, McNeel DG, Thompson JA, Gupta S, Leidner R, Wang-Gillam A, Parikh NS, Long D, Kurtulus S, Ho Lee L, Chowdhury NR, Bender F, Pavlakis GN. Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors. J Immunother Cancer 2021; 9:jitc-2021-003388. [PMID: 34799399 PMCID: PMC8606766 DOI: 10.1136/jitc-2021-003388] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2021] [Indexed: 11/30/2022] Open
Abstract
Background NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors. Methods Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1). Results As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1–77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8+ T cells), increased CD16+ monocytes, and increased CD163+ macrophages at injection sites. Conclusions Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy. Trial registration number NCT02452268.
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Affiliation(s)
- Kevin Conlon
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Dionysios C Watson
- Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.,University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Thomas A Waldmann
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Antonio Valentin
- Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA
| | - Cristina Bergamaschi
- Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Barbara K Felber
- Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Cody J Peer
- Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - William D Figg
- Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA
| | - E Lake Potter
- Vaccine Research Center, NIAID, Bethesda, Maryland, USA
| | | | - Douglas G McNeel
- Carbone Cancer Center, University of Wisconsin Madison, Madison, Wisconsin, USA
| | | | - Sumati Gupta
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Rom Leidner
- Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA
| | - Andrea Wang-Gillam
- Division of Oncology, Department of Medicine, Washington University in Saint Louis, St Louis, Missouri, USA
| | - Nehal S Parikh
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Debby Long
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Sema Kurtulus
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - Lang Ho Lee
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | | | - Florent Bender
- Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
| | - George N Pavlakis
- Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA
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45
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Kurianowicz K, Klatka M, Polak A, Hymos A, Bębnowska D, Podgajna M, Hrynkiewicz R, Sierawska O, Niedźwiedzka-Rystwej P. Impaired Innate Immunity in Pediatric Patients Type 1 Diabetes-Focus on Toll-like Receptors Expression. Int J Mol Sci 2021; 22:12135. [PMID: 34830017 PMCID: PMC8625857 DOI: 10.3390/ijms222212135] [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: 09/23/2021] [Revised: 10/23/2021] [Accepted: 10/27/2021] [Indexed: 01/07/2023] Open
Abstract
Type 1 diabetes (DM1) is classified as an autoimmune disease. An uncontrolled response of B and T lymphocytes to the body's own tissues develops in the absence of immune tolerance. The main aim of the study was to evaluate the effect of the duration of type 1 diabetes in children on the expression of TLR receptors and the relationship with the parameters of glycemic control in patients. As a result, we showed significant differences in the level of TLR2, TLR4 and TLR9 expression in patients with DM1 in the early stage of the disease and treated chronically compared to the healthy group. Additionally, in this study, we found that the numbers of CD19+ B cells, CD3+ CD4+, CD3+ CD8+ T cells and NK cells are different for newly diagnosed DM1 individuals, patients receiving chronic treatment and for healthy controls, indicating an important role of these cells in killing pancreatic beta cells. Moreover, higher levels of IL-10 in patients with newly diagnosed DM1 have also been found, confirming the reports found in the literature.
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MESH Headings
- Adolescent
- Antigens, CD19/genetics
- Antigens, CD19/immunology
- B-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/pathology
- Child
- Child, Preschool
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Female
- Gene Expression Regulation/genetics
- Humans
- Immunity, Innate/genetics
- Immunity, Innate/immunology
- Interleukin-10/genetics
- Interleukin-10/immunology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Male
- Pediatrics
- Toll-Like Receptor 2/genetics
- Toll-Like Receptor 4/genetics
- Toll-Like Receptor 9/genetics
- Toll-Like Receptors/genetics
- Toll-Like Receptors/immunology
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Affiliation(s)
- Katarzyna Kurianowicz
- Department of Pediatric Endocrinology and Diabetology, Medical University of Lublin, Gębali 1 St., 20-093 Lublin, Poland; (K.K.); (M.K.)
| | - Maria Klatka
- Department of Pediatric Endocrinology and Diabetology, Medical University of Lublin, Gębali 1 St., 20-093 Lublin, Poland; (K.K.); (M.K.)
| | - Agnieszka Polak
- Department of Endocrinology, Medical University of Lublin, Jaczewskiego 8 St., 20-954 Lublin, Poland;
| | - Anna Hymos
- Department of Experimental Immunology, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland;
| | - Dominika Bębnowska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (D.B.); (R.H.); (O.S.)
| | - Martyna Podgajna
- Department of Clinica Immunology and Immunotherapy, Medical University of Lublin, Chodźki 4a St., 20-093 Lublin, Poland;
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (D.B.); (R.H.); (O.S.)
| | - Olga Sierawska
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; (D.B.); (R.H.); (O.S.)
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46
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Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M, Nguyen V, Tamaki SJ, Tamaki W, Tamaki CM, Mehdizadeh M, Putnam AL, Spitzer MH, Ye CJ, Tang Q, Bluestone JA. The effects of low-dose IL-2 on Treg adoptive cell therapy in patients with Type 1 diabetes. JCI Insight 2021; 6:e147474. [PMID: 34324441 PMCID: PMC8492314 DOI: 10.1172/jci.insight.147474] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 07/28/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND A previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells. METHODS Patients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations’ phenotypes over time. RESULTS Multiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations. CONCLUSION These data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity. TRIAL REGISTRATION ClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial). FUNDING Sean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.
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Affiliation(s)
- Shen Dong
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Kamir J Hiam-Galvez
- Parker Institute for Cancer Immunotherapy, UCSF, San Francisco, United States of America
| | - Cody T Mowery
- Institute for Human Genetics, UCSF, San Francisco, United States of America
| | - Kevan C Herold
- Department of Immunobiology, Yale University School of Medicine, New Haven, United States of America
| | - Stephen E Gitelman
- Division Pediatric Endocrinology and Diabetes Center, UCSF, San Francisco, United States of America
| | - Jonathan H Esensten
- Department of Laboratory Medicine, UCSF, San Francisco, United States of America
| | - Weihong Liu
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Angela P Lares
- Diabetes Center, UCSF, San Francisco, United States of America
| | | | - Michael Lee
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Vinh Nguyen
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Stanley J Tamaki
- Flow Cytometry Core Parnassus, UCSF, San Francisco, United States of America
| | - Whitney Tamaki
- Diabetes Center, UCSF, San Francisco, United States of America
| | | | | | - Amy L Putnam
- Diabetes Center, UCSF, San Francisco, United States of America
| | - Matthew H Spitzer
- Department of Otolaryngology, UCSF, San Francisco, United States of America
| | - C Jimmie Ye
- Institute for Human Genetics, UCSF, San Francisco, United States of America
| | - Qizhi Tang
- Division of Transplant Surgery, UCSF, San Francisco, United States of America
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47
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Piotrowska M, Gliwiński M, Trzonkowski P, Iwaszkiewicz-Grzes D. Regulatory T Cells-Related Genes Are under DNA Methylation Influence. Int J Mol Sci 2021; 22:7144. [PMID: 34281195 PMCID: PMC8267835 DOI: 10.3390/ijms22137144] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells (Tregs) exert a highly suppressive function in the immune system. Disturbances in their function predispose an individual to autoimmune dysregulation, with a predominance of the pro-inflammatory environment. Besides Foxp3, which is a master regulator of these cells, other genes (e.g., Il2ra, Ctla4, Tnfrsf18, Ikzf2, and Ikzf4) are also involved in Tregs development and function. Multidimensional Tregs suppression is determined by factors that are believed to be crucial in the action of Tregs-related genes. Among them, epigenetic changes, such as DNA methylation, tend to be widely studied over the past few years. DNA methylation acts as a repressive mark, leading to diminished gene expression. Given the role of increased CpG methylation upon Tregs imprinting and functional stability, alterations in the methylation pattern can cause an imbalance in the immune response. Due to the fact that epigenetic changes can be reversible, so-called epigenetic modifiers are broadly used in order to improve Tregs performance. In this review, we place emphasis on the role of DNA methylation of the genes that are key regulators of Tregs function. We also discuss disease settings that have an impact on the methylation status of Tregs and systematize the usefulness of epigenetic drugs as factors able to influence Tregs functions.
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Affiliation(s)
| | | | | | - Dorota Iwaszkiewicz-Grzes
- Department of Medical Immunology, Medical University of Gdansk, 80-210 Gdańsk, Poland; (M.P.); (M.G.); (P.T.)
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48
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Miao M, Li Y, Huang B, Chen J, Jin Y, Shao M, Zhang X, Sun X, He J, Li Z. Treatment of Active Idiopathic Inflammatory Myopathies by Low-Dose Interleukin-2: A Prospective Cohort Pilot Study. Rheumatol Ther 2021; 8:835-847. [PMID: 33852146 PMCID: PMC8217480 DOI: 10.1007/s40744-021-00301-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 03/17/2021] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION Treatment of idiopathic inflammatory myopathies (IIMs) is challenging due to a lack of safe and efficacious medication. Low-dose interleukin-2 (IL-2) treatment emerges as a new option in active IIMs. This study aims to explore the clinical and immunological effects of low-dose IL-2 in patients with active IIMs. METHODS Eighteen patients with active IIMs were enrolled and received 1 × 106 IU of IL-2 subcutaneously every other day for 12 weeks on top of standard care. The primary endpoint for the trial was change in percentage of regulatory T (Treg) cells in total CD4+ T cells at week 12. The secondary endpoints included the International Myositis Assessment and Clinical Studies (IMACS) definition of improvement (DOI), the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria, safety, and steroid-sparing effect at weeks 12 and 24. RESULTS With low-dose IL-2 treatment, 77.78% (14/18) patients achieved IMACS DOI and 83.33% (15/18) patients met the 2016 ACR/EULAR myositis response criteria at week 12. All individual core set measures (CSMs) including PhGA, PGA and HAQ-DI, muscle enzymes, MMT-8 and extramuscular activity were improved at week 12. The cutaneous dermatomyositis disease area and severity index activity score (CDASI-a) decreased significantly from 7 (4.5, 13) to 2 (0, 7) after IL-2 administration (P < 0.001). Proportion of Treg cells significantly increased with low-dose IL-2 treatment at week 12 (8.97% [5.77, 9.89%] vs. 15.2% [10.4, 17.3%], P = 0.009). There were no serious adverse events. CONCLUSIONS Low-dose IL-2 was effective in active IIMs and well tolerated. The amelioration of disease activity may associate with promotion of Tregs. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04062019.
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Affiliation(s)
- Miao Miao
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuhui Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Bo Huang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jiali Chen
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yuebo Jin
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Miao Shao
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xia Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiaolin Sun
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, 100044, China.
- Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China.
- Peking-Tsinghua Center for Life Sciences, Beijing, China.
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49
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Lo Preiato V, Salvagni S, Ricci C, Ardizzoni A, Pagotto U, Pelusi C. Diabetes mellitus induced by immune checkpoint inhibitors: type 1 diabetes variant or new clinical entity? Review of the literature. Rev Endocr Metab Disord 2021; 22:337-349. [PMID: 33409866 DOI: 10.1007/s11154-020-09618-w] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2020] [Indexed: 12/16/2022]
Abstract
Immune Check-Point Inhibitors (CPIs) have improved long-term patients' outcomes in several advanced cancers. Diabetes mellitus induced by CPIs (CPI-DM) is considered the second most frequent endocrine CPIs' side effects with a variable prevalence up to 2%. The aim of our study was to identify CPI-DM characteristics and differences from the classical form of diabetes. Therefore, we conducted a structured Pubmed® search collecting publications dated from January 2015 to December 2019. A total of 642 citations were identified and 121 publications met our study criteria. We analyzed 200 case reports, including our 3 cases under publication. The majority of CPI-DM occurred with anti-Programmed cell Death-1 in monotherapy or in combination, although few cases with Programmed cell Death Ligand-1 and Cytotoxic T Lymphocyte Antigen 4 were reported. Generally, CPI-DM arose early (an average of 9 weeks after CPIs starting), but also after the end of CPIs treatment. In all patients, CPI-DM has an acute onset and in 67.5% of cases diabetic ketoacidosis occurs. C-peptide levels were usually and permanently compromised, requiring lifelong insulin therapy. Moreover, autoimmunity and genetic profile was not always helpful. In particular, anti-glutamic acid decarboxylase (anti-GAD) antibodies and Human Leukocyte Antigen (HLA) DR4 were present in only 43.0% and 51.3% of cases respectively. In 51.0% of subjects a mild exocrine impairment coexisted. In short, though CPI-DM has similarities to type 1 diabetes mellitus, it represents a new, largely unknown, clinical entity. In addition, as CPI-DM is a relative frequent side-effect under CPI, a close monitoring of the glucose levels and early signs and symptoms of diabetes in patients affected by neoplasm is recommended.
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Affiliation(s)
- V Lo Preiato
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
| | - S Salvagni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - C Ricci
- Surgical Department, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola Hospital, Bologna, Italy
| | - A Ardizzoni
- Division of Medical Oncology, Department of Experimental Diagnostic and Speciality Medicine (DIMES), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Bologna, Italy
| | - U Pagotto
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy.
| | - C Pelusi
- Endocrinology Unit and Prevention and Care of Diabetes, Department of Medical and Surgical Science (DIMEC), Alma Mater Studiorum, University of Bologna, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy
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50
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Bettini M, Bettini ML. Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes. Diabetes 2021; 70:1211-1219. [PMID: 34016597 PMCID: PMC8275894 DOI: 10.2337/dbi18-0058] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/10/2021] [Indexed: 12/22/2022]
Abstract
Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.
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MESH Headings
- Animals
- Autoimmunity/physiology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 1/therapy
- Endocrinology/methods
- Endocrinology/trends
- Humans
- Immune Tolerance/physiology
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/trends
- Mice
- Molecular Targeted Therapy/methods
- Molecular Targeted Therapy/trends
- Pancreas/immunology
- Pancreas/metabolism
- Pancreas/pathology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/physiology
- T-Lymphocytes, Regulatory/transplantation
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Affiliation(s)
- Maria Bettini
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT
| | - Matthew L Bettini
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT
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