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Askarizadeh F, Butler AE, Kesharwani P, Sahebkar A. Regulatory effect of curcumin on CD40:CD40L interaction and therapeutic implications. Food Chem Toxicol 2025; 200:115369. [PMID: 40043936 DOI: 10.1016/j.fct.2025.115369] [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: 11/14/2024] [Revised: 01/24/2025] [Accepted: 03/02/2025] [Indexed: 04/21/2025]
Abstract
Natural compounds have garnered significant attention as potential therapeutic agents due to their inherent properties. Their notable qualities, including safety, efficacy, favorable pharmacokinetic properties, and heightened effectiveness against certain diseases, particularly inflammatory conditions, make them particularly appealing. Among these compounds, curcumin has attracted considerable interest for its unique therapeutic properties and has therefore been extensively studied as a potential therapeutic agent for treating various diseases. Curcumin exhibits diverse anti-inflammatory, antioxidant, and antimicrobial effects. Curcumin's immune system regulatory ability has made it a promising compound for treatment of various inflammatory diseases, such as psoriasis, atherosclerosis, asthma, colitis, IBD, and arthritis. Among the signaling pathways implicated in these conditions, the CD40 receptor together with its ligand, CD40L, are recognized as central players. Studies have demonstrated that the interaction between CD40 and CD40L interaction acts as the primary mediator of the immune response in inflammatory diseases. Numerous studies have explored the impact of curcumin on the CD40:CD40L pathway, highlighting its regulatory effects on this inflammatory pathway and its potential therapeutic use in related inflammatory conditions. In this review, we will consider the evidence concerning curcumin's modulatory effects in inflammatory disease and its potential therapeutic role in regulating the CD40:CD40L pathway.
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Affiliation(s)
- Fatemeh Askarizadeh
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospitals, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Wu X, Xing J, Tang X, Sheng X, Chi H, Zhan W. Interaction between interleukin-12 (IL-12) and its receptor (IL-12Rβ2) mediates CD4 + T cell subsets activation in flounder (Paralichthys olivaceus). Int J Biol Macromol 2025; 293:139302. [PMID: 39743087 DOI: 10.1016/j.ijbiomac.2024.139302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
Interleukin-12 (IL-12) regulates the differentiation of CD4+ T lymphocytes into Th1 cells by binding to its receptor, thereby promoting cellular immunity. This study characterized IL-12 and its receptor β2 (IL-12Rβ2) in flounder (Paralichthys olivaceus) and investigated their interaction, effects on T cell proliferation and differentiation, and the adjuvant effects of IL-12. The recombinant IL-12 was successfully expressed, and the IL-12Rβ2 antibody was confirmed to specifically recognize IL-12Rβ2. IL-12 bound to IL-12Rβ2 at the cellular level. IL-12 stimulation increased leukocyte proliferation and the proportion of CD4+/IL-12Rβ2+ cells. Moreover, blocking IL-12Rβ2 with antibody reduced Th1 markers (STAT4, T-bet, IFN-γ) and increased Th2 markers (JAK3, STAT6, GATA3). Immunization with rOmpV+IL-12 significantly upregulated CD4+/IFN-γ+ cells on day seven, peaked the sIgM+ B lymphocyte response in the fourth week, and enhanced survival after Edwardsiella tarda challenge. In conclusion, IL-12 signaling effectively facilitates the differentiation of Th1 cells and negatively impacts the function of Th2 cells in flounder. This study provides new insights into the immune regulation of CD4+ T cells in teleosts and lays the foundation for understanding the cellular immune mechanisms of vaccines in aquaculture.
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Affiliation(s)
- Xiaoyan Wu
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China
| | - Jing Xing
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China.
| | - Xiaoqian Tang
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China
| | - Xiuzhen Sheng
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China
| | - Heng Chi
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China
| | - Wenbin Zhan
- Laboratory of Pathology and Immunology of Aquatic Animals, KLMME, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, Shandong 266237, China
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Zhao Y, Liu J, Peng C, Guo S, Wang B, Chen L, Wang Y, Tang H, Liu L, Pan Q, Li S, Wang J, Yang D, Du E. Cross-protection against homo and heterologous influenza viruses via intranasal administration of an HA chimeric multiepitope nanoparticle vaccine. J Nanobiotechnology 2025; 23:77. [PMID: 39905416 PMCID: PMC11792681 DOI: 10.1186/s12951-025-03122-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Influenza A viruses (IAVs) cause seasonal influenza epidemics and pose significant threats to public health. However, seasonal influenza vaccines often elicit strain-specific immune responses and confer little protection against mismatched strains. There is an urgent need to develop universal influenza vaccines against emerging and potentially re-emerging influenza virus infections. Multiepitope vaccines combining multiple conserved epitopes can induce more robust and broader immune responses and provide a potential solution. RESULTS Here, we demonstrated that an HA chimeric multiepitope nanoparticle vaccine, delivered intranasally conferred broad protection against challenges with various influenza viruses in mice. The nanoparticle vaccine co-expresses the ectodomain of haemagglutinin (H), three repeated highly conserved ectodomains of matrix protein 2 (M), and the M-cell-targeting ligand Co4B (C) in a baculovirus-insect cell system. These elements (C, H and M) were presented on the surface of self-assembling ferritin (f) in tandem to generate a nanoparticle denoted as CHM-f. Intranasal vaccination with CHM-f nanoparticles elicited robust humoral and cellular immune responses, conferring complete protection against a variety of IAVs, including the A/PR8/34 H1N1 strain, the swine flu H3N2 strain, the avian flu H5N8 strain, and H9N2. When CHM-f nanoparticles adjuvanted with CpG IAMA-002, the weight loss protective effect, cellular immune responses and mucosal IgA responses were significantly augmented. Compared with controls, mice immunized with CHM-f nanoparticles with or without CpG IAMA-002 showed significant reductions in weight loss, lung viral titres and pathological changes. CONCLUSIONS These results suggest that CHM-f nanoparticle with or without CpG IAMA-002 is a promising candidate as a universal influenza vaccine.
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Affiliation(s)
- Yongqiang Zhao
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Jia Liu
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Chun Peng
- Chengdu NanoVAX Biotechnology Co., Ltd., Chengdu, Sichuan, 610219, China
| | - Shuangshuang Guo
- Yangling Carey Biotechnology Co., Ltd., Yangling, Shaanxi, 712100, China
| | - Bo Wang
- Yangling Carey Biotechnology Co., Ltd., Yangling, Shaanxi, 712100, China
| | - Longping Chen
- Yangling Carey Biotechnology Co., Ltd., Yangling, Shaanxi, 712100, China
| | - Yating Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Haiwen Tang
- Chengdu NanoVAX Biotechnology Co., Ltd., Chengdu, Sichuan, 610219, China
| | - Liming Liu
- Nanjing JSIAMA Biopharmaceuticals Ltd., Nanjing, Jiangsu, 210000, China
| | - Qi Pan
- Nanjing JSIAMA Biopharmaceuticals Ltd., Nanjing, Jiangsu, 210000, China
| | - Shiren Li
- Chengdu NanoVAX Biotechnology Co., Ltd., Chengdu, Sichuan, 610219, China
| | - Jingyu Wang
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China
| | - Dongni Yang
- Chengdu NanoVAX Biotechnology Co., Ltd., Chengdu, Sichuan, 610219, China.
| | - Enqi Du
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, 712100, China.
- Yangling Carey Biotechnology Co., Ltd., Yangling, Shaanxi, 712100, China.
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Shamseldin MM, Read KA, Hall JM, Tuazon JA, Brown JM, Guo M, Gupta YA, Deora R, Oestreich KJ, Dubey P. The adjuvant BcfA activates antigen presenting cells through TLR4 and supports T FH and T H1 while attenuating T H2 gene programming. Front Immunol 2024; 15:1439418. [PMID: 39267766 PMCID: PMC11390363 DOI: 10.3389/fimmu.2024.1439418] [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: 05/27/2024] [Accepted: 08/09/2024] [Indexed: 09/15/2024] Open
Abstract
Introduction Adjuvants added to subunit vaccines augment antigen-specific immune responses. One mechanism of adjuvant action is activation of pattern recognition receptors (PRRs) on innate immune cells. Bordetella colonization factor A (BcfA); an outer membrane protein with adjuvant function, activates TH1/TH17-polarized immune responses to protein antigens from Bordetella pertussis and SARS CoV-2. Unlike other adjuvants, BcfA does not elicit a TH2 response. Methods To understand the mechanism of BcfA-driven TH1/TH17 vs. TH2 activation, we screened PRRs to identify pathways activated by BcfA. We then tested the role of this receptor in the BcfA-mediated activation of bone marrow-derived dendritic cells (BMDCs) using mice with germline deletion of TLR4 to quantify upregulation of costimulatory molecule expression and cytokine production in vitro and in vivo. Activity was also tested on human PBMCs. Results PRR screening showed that BcfA activates antigen presenting cells through murine TLR4. BcfA-treated WT BMDCs upregulated expression of the costimulatory molecules CD40, CD80, and CD86 and produced IL-6, IL-12/23 p40, and TNF-α while TLR4 KO BMDCs were not activated. Furthermore, human PBMCs stimulated with BcfA produced IL-6. BcfA-stimulated murine BMDCs also exhibited increased uptake of the antigen DQ-OVA, supporting a role for BcfA in improving antigen presentation to T cells. BcfA further activated APCs in murine lungs. Using an in vitro TH cell polarization system, we found that BcfA-stimulated BMDC supernatant supported TFH and TH1 while suppressing TH2 gene programming. Conclusions Overall, these data provide mechanistic understanding of how this novel adjuvant activates immune responses.
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Affiliation(s)
- Mohamed M. Shamseldin
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
- Departments of Microbiology, The Ohio State University, Columbus, OH, United States
- Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University-Ain Helwan, Helwan, Egypt
| | - Kaitlin A. Read
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Jesse M. Hall
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Jasmine A. Tuazon
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Jessica M. Brown
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Myra Guo
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Yash A. Gupta
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
| | - Rajendar Deora
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
- Departments of Microbiology, The Ohio State University, Columbus, OH, United States
| | - Kenneth J. Oestreich
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States
| | - Purnima Dubey
- Departments of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, United States
- Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
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Troise D, Infante B, Mercuri S, Catalano V, Ranieri E, Stallone G. Dendritic Cells: A Bridge between Tolerance Induction and Cancer Development in Transplantation Setting. Biomedicines 2024; 12:1240. [PMID: 38927447 PMCID: PMC11200833 DOI: 10.3390/biomedicines12061240] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 05/23/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Dendritic cells (DCs) are a heterogeneous group of antigen-presenting cells crucial for fostering allograft tolerance while simultaneously supporting host defense against infections and cancer. Within the tumor microenvironment, DCs can either mount an immune response against cancer cells or foster immunotolerance, presenting a dual role. In immunocompromised individuals, posttransplant malignancies pose a significant health concern, with DCs serving as vital players in immune responses against cancer cells. Both recipient- and donor-derived DCs play a critical role in the rejection process, infiltrating the transplanted organ and sustaining T-cell responses. The use of immunosuppressive drugs represents the predominant approach to control this immunological barrier in transplanted organs. Evidence has shed light on the immunopharmacology of these drugs and novel strategies for manipulating DCs to promote allograft survival. Therefore, comprehending the mechanisms underlying this intricate microenvironment and the effects of immunosuppressive therapy on DCs is crucial for developing targeted therapies to reduce graft failure rates. This review will delve into the fundamental immunobiology of DCs and provide a detailed exploration of their clinical significance concerning alloimmune responses and posttransplant malignancies.
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Affiliation(s)
- Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
- Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 52 Stockholm, Sweden
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Valeria Catalano
- Unit of Clinical Pathology, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Elena Ranieri
- Unit of Clinical Pathology, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy
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Gautam N, Ramamoorthi G, Champion N, Han HS, Czerniecki BJ. Reviewing the significance of dendritic cell vaccines in interrupting breast cancer development. Mol Aspects Med 2024; 95:101239. [PMID: 38150884 DOI: 10.1016/j.mam.2023.101239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/29/2023]
Abstract
Breast cancer is a heterogeneous disease and is the most prevalent cancer in women. According to the U.S breast cancer statistics, about 1 in every 8 women develop an invasive form of breast cancer during their lifetime. Immunotherapy has been a significant advancement in the treatment of cancer with multiple studies reporting favourable patient outcomes by modulating the immune response to cancer cells. Here, we review the significance of dendritic cell vaccines in treating breast cancer patients. We discuss the involvement of dendritic cells and oncodrivers in breast tumorigenesis, highlighting the rationale for targeting oncodrivers and neoantigens using dendritic cell vaccine therapy. We review different dendritic cell subsets and maturation states previously used to develop vaccines and suggest the use of DC vaccines for breast cancer prevention. Further, we highlight that the intratumoral delivery of type 1 dendritic cell vaccines in breast cancer patients activates tumor antigen-specific CD4+ T helper cell type 1 (Th1) cells, promoting an anti-tumorigenic immune response while concurrently blocking pro-tumorigenic responses. In summary, this review provides an overview of the current state of dendritic cell vaccines in breast cancer highlighting the challenges and considerations necessary for an efficient dendritic cell vaccine design in interrupting breast cancer development.
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Affiliation(s)
- Namrata Gautam
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Ganesan Ramamoorthi
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Nicholas Champion
- Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Hyo S Han
- Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Brian J Czerniecki
- Clinical Science & Immunology Program, H. Lee Moffitt Cancer Center, Tampa, FL, USA; Department of Breast Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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Nery GB, de Araujo CAR, da Silva GB, Bittar H, Bordallo VP, Amaral JB, Hardt M, Marti L, Birbrair A, Jimenez M, Bastos MF, Nali LHS, Longo PL, Laurentino GC, Bachi ALL, Heller D. Impact of social distancing from the COVID-19 pandemic on the immuno-inflammatory response of older adults. BMC Geriatr 2024; 24:99. [PMID: 38273281 PMCID: PMC10811891 DOI: 10.1186/s12877-024-04699-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 01/11/2024] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND Older adults, as the population considered at increased risk for severe COVID-19, were the most impacted by social isolation. Thus, this study aimed to assess the salivary immune/inflammatory response of older adults before and during the COVID-19 pandemic. METHODS A cohort of 11 older adults (mean age 66.8 ± 6.1) was followed at three different time points: before (S1) and after 6 (S2) and 20 months (S3) of the beginning of the COVID-19 pandemic in Brazil. Unstimulated saliva samples were obtained to assess the levels of antibodies (secretory IgA, IgG and IgM) by ELISA and cytokines (IL-2, IL-5, IL-6, IL-8 and IL-10, TSLP, IFN-γ, TNF-α) by multiplex analysis. Significant differences were evaluated using the Kruskal-Wallis test with Dunn's post-test. RESULTS None volunteer presented periodontal disease or caries. All volunteers received at least two doses of the COVID-19 vaccines after S2 and before S3. A tendency to increase salivary levels of SIgA and IgM at S2 and of IgG at S3 were observed compared to the values found at S1 and S2. Significantly decreased levels of IL-2 and IL-5 were found at S2 and S3 (p < 0.001) time points. Lower levels of IFN-γ were found at S2 as compared to the values observed at S1 (p < 0.01). A significant decrease in the IFN-γ/IL-10 ratio was found at S2 (p < 0.01). When assessing the Th1/Th2 ratios, a significant decrease was found in the IFN-γ/TSLP ratio at S2 (p < 0.001) and S3 (p < 0.001) when compared to the values at S1. In addition, a significant increase was observed in the TNF-α/IL-5 ratio at S2 (p < 0.001) and S3 (p < 0.001) in comparison to the values at S1. In a similar way, an increase in the TNF-α/IL-6 ratio (Fig. 5E) was observed at S3 (p < 0.001) when compared to the values at S1. CONCLUSIONS Overall, this study provides valuable insights into the impact of COVID-19-induced social isolation on immune/inflammatory responses in the upper airway mucosa, particularly those present in oral cavity, of older adults. It demonstrates that a controlled shift in Th1 and Th2 immune responses, both during infection and post-vaccination, can create favorable conditions to combat viral infections without exacerbating the immune response or worsening the pathology.
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Affiliation(s)
- Giulia Beletato Nery
- Post Graduate Program in Dentistry, Cruzeiro Do Sul University, São Paulo, Brazil
| | | | | | - Helena Bittar
- Post Graduate Program in Dentistry, Cruzeiro Do Sul University, São Paulo, Brazil
| | | | - Jônatas B Amaral
- Department of Otorhinolaryngology, ENT Lab, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil
| | - Markus Hardt
- Center for Salivary Diagnostics, The Forsyth Institute, Cambridge, MA, USA
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA
| | - Luciana Marti
- Experimental Research, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Alexander Birbrair
- Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Manuel Jimenez
- Departamento de Didáctica de La Educación Física y Salud, Universidad Internacional de La Rioja, Logroño, Spain
| | - Marta Ferreira Bastos
- Postgraduate Program in Aging Sciences, São Judas Tadeu University, São Paulo, Brazil
| | - Luiz Henrique Silva Nali
- Department of Otorhinolaryngology, ENT Lab, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil
- Post-Graduate Program in Health Science, Santo Amaro University (UNISA), Santo Amaro, Brazil
| | | | | | - André L L Bachi
- Department of Otorhinolaryngology, ENT Lab, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil.
- Post-Graduate Program in Health Science, Santo Amaro University (UNISA), Santo Amaro, Brazil.
| | - Debora Heller
- Post Graduate Program in Dentistry, Cruzeiro Do Sul University, São Paulo, Brazil.
- Experimental Research, Hospital Israelita Albert Einstein, São Paulo, Brazil.
- Department of Periodontology, UT Health San Antonio, San Antonio, TX, USA.
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Logghe T, van Zwol E, Immordino B, Van den Cruys K, Peeters M, Giovannetti E, Bogers J. Hyperthermia in Combination with Emerging Targeted and Immunotherapies as a New Approach in Cancer Treatment. Cancers (Basel) 2024; 16:505. [PMID: 38339258 PMCID: PMC10854776 DOI: 10.3390/cancers16030505] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/10/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Despite significant advancements in the development of novel therapies, cancer continues to stand as a prominent global cause of death. In many cases, the cornerstone of standard-of-care therapy consists of chemotherapy (CT), radiotherapy (RT), or a combination of both. Notably, hyperthermia (HT), which has been in clinical use in the last four decades, has proven to enhance the effectiveness of CT and RT, owing to its recognized potency as a sensitizer. Furthermore, HT exerts effects on all steps of the cancer-immunity cycle and exerts a significant impact on key oncogenic pathways. Most recently, there has been a noticeable expansion of cancer research related to treatment options involving immunotherapy (IT) and targeted therapy (TT), a trend also visible in the research and development pipelines of pharmaceutical companies. However, the potential results arising from the combination of these innovative therapeutic approaches with HT remain largely unexplored. Therefore, this review aims to explore the oncology pipelines of major pharmaceutical companies, with the primary objective of identifying the principal targets of forthcoming therapies that have the potential to be advantageous for patients by specifically targeting molecular pathways involved in HT. The ultimate goal of this review is to pave the way for future research initiatives and clinical trials that harness the synergy between emerging IT and TT medications when used in conjunction with HT.
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Affiliation(s)
- Tine Logghe
- Elmedix NV, Dellingstraat 34/1, 2800 Mechelen, Belgium
| | - Eke van Zwol
- Elmedix NV, Dellingstraat 34/1, 2800 Mechelen, Belgium
| | - Benoît Immordino
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, San Giuliano, 56017 Pisa, Italy
- Institute of Life Sciences, Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
| | | | - Marc Peeters
- Department of Oncology, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Elisa Giovannetti
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, San Giuliano, 56017 Pisa, Italy
- Department of Medical Oncology, Amsterdam UMC, Location Vrije Universiteit, Cancer Center Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Johannes Bogers
- Elmedix NV, Dellingstraat 34/1, 2800 Mechelen, Belgium
- Laboratory of Cell Biology and Histology, Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium
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Bernardo L, Solana JC, Sánchez C, Torres A, Reyes-Cruz EY, Carrillo E, Moreno J. Immunosuppressants alter the immune response associated with Glucantime ® treatment for Leishmania infantum infection in a mouse model. Front Immunol 2023; 14:1285943. [PMID: 38106411 PMCID: PMC10722182 DOI: 10.3389/fimmu.2023.1285943] [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: 08/30/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
Background Immunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop. Objectives To examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses. Results Immunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment. Conclusion The immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients.
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Affiliation(s)
- Lorena Bernardo
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Jose Carlos Solana
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Sánchez
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
| | - Ana Torres
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Eder Yaveth Reyes-Cruz
- LADISER Immunology and Molecular Biology, Faculty of Chemical Sciences, Universidad Veracruzana, Orizaba, Veracruz, Mexico
| | - Eugenia Carrillo
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Moreno
- WHO Collaborating Centre for Leishmaniasis, National Center for Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
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10
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Xie D, Feng Z, Yang W, Wang Y, Li R, Zhang S, Zhou Z. A mAb to SIRPα downregulates the priming of naive CD4 + T cell in Primary immune thrombocytopenia. Cell Immunol 2023; 391-392:104757. [PMID: 37660478 DOI: 10.1016/j.cellimm.2023.104757] [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: 04/06/2023] [Accepted: 08/17/2023] [Indexed: 09/05/2023]
Abstract
SIRPα is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on monocytes, dendritic cells, and macrophages. Studies recently showed that SIRPα is essential for priming of CD4 + T cells by DCs and for development of Th17 cell-mediated autoimmune diseases. We have now further evaluated the importance of SIRPα and that of its ligand CD47 in primary immune thrombocytopenia (ITP). In this study, we show that there was a low expression state of SIRPα on the surface of monocytes. Treatment of cells culture from ITP patients with a mAb to SIRPα that blocks the binding of SIRPα to CD47 downregulated the ITP response. The abilities of monocytes from ITP patients to stimulate an allogenic MLR were reduced. The proliferation of, and production of IL-2, by CD4 + T cells from ITP patients were inhibited, the Treg cell numbers and the production of IL-10 pairs were upregulated, and the production of TGF-β not was inhibited, by a mAb to SIRPα. Moreover, a mAb to SIRPα, the expression of HLA-DR and CD86 were markedly inhibited and the expression of CD80 was slightly upregulated, on the surface of CD14 + monocytes from ITP patients as compared with healthy subjects. However, blockade of SIRPα increased the secretion of TLR-dependent cytokines TNF-α, IL-6 and IL-1β by PBMCs, which may be considered as a reserve in response to danger signals. These results suggest that SIRPα on monocytes is essential for the priming of naive T cells and the development of ITP. Therefore, SIRPα is a potential therapeutic target for ITP and other autoimmune diseases.
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Affiliation(s)
- Dongmei Xie
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Zhihui Feng
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Wen Yang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Yacan Wang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Renxia Li
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Shiqi Zhang
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China
| | - Zeping Zhou
- Department of Hematology, The Second Affiliated Hospital of Kunming Medical University, Yunnan, China.
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11
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Lee KW, Yam JWP, Mao X. Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations. Cells 2023; 12:2147. [PMID: 37681880 PMCID: PMC10486560 DOI: 10.3390/cells12172147] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
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Affiliation(s)
- Kyu-Won Lee
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
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12
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Werninghaus IC, Hinke DM, Fossum E, Bogen B, Braathen R. Neuraminidase delivered as an APC-targeted DNA vaccine induces protective antibodies against influenza. Mol Ther 2023; 31:2188-2205. [PMID: 36926694 PMCID: PMC10362400 DOI: 10.1016/j.ymthe.2023.03.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 02/01/2023] [Accepted: 03/12/2023] [Indexed: 03/18/2023] Open
Abstract
Conventional influenza vaccines focus on hemagglutinin (HA). However, antibody responses to neuraminidase (NA) have been established as an independent correlate of protection. Here, we introduced the ectodomain of NA into DNA vaccines that, as translated dimeric vaccine proteins, target antigen-presenting cells (APCs). The targeting was mediated by an single-chain variable fragment specific for major histocompatibility complex (MHC) class II, which is genetically linked to NA via a dimerization motif. A single immunization of BALB/c mice elicited strong and long-lasting NA-specific antibodies that inhibited NA enzymatic activity and reduced viral replication. Vaccine-induced NA immunity completely protected against a homologous influenza virus and out-competed NA immunity induced by a conventional inactivated virus vaccine. The protection was mainly mediated by antibodies, although NA-specific T cells also contributed. APC-targeting and antigen bivalency were crucial for vaccine efficacy. The APC-targeted vaccine was potent at low doses of DNA, indicating a dose-sparing effect. Similar results were obtained with NA vaccines that targeted different surface molecules on dendritic cells. Interestingly, the protective efficacy of NA as antigen compared favorably with HA and therefore ought to receive more attention in influenza vaccine research.
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Affiliation(s)
- Ina Charlotta Werninghaus
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway; Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, 0372 Oslo, Norway.
| | - Daniëla Maria Hinke
- Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, 0372 Oslo, Norway
| | - Even Fossum
- Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, 0372 Oslo, Norway
| | - Bjarne Bogen
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway; Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, 0372 Oslo, Norway
| | - Ranveig Braathen
- Department of Immunology, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway; Division of Laboratory Medicine, Department of Immunology, Oslo University Hospital, 0372 Oslo, Norway.
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13
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Yadagiri G, Singh A, Arora K, Mudavath SL. Immunotherapy and immunochemotherapy in combating visceral leishmaniasis. Front Med (Lausanne) 2023; 10:1096458. [PMID: 37265481 PMCID: PMC10229823 DOI: 10.3389/fmed.2023.1096458] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 04/14/2023] [Indexed: 06/03/2023] Open
Abstract
Visceral leishmaniasis (VL), a vector-borne disease, is caused by an obligate intramacrophage, kinetoplastid protozoan parasite of the genus Leishmania. Globally, VL is construed of diversity and complexity concerned with high fatality in tropics, subtropics, and Mediterranean regions with ~50,000-90,000 new cases annually. Factors such as the unavailability of licensed vaccine(s), insubstantial measures to control vectors, and unrestrained surge of drug-resistant parasites and HIV-VL co-infections lead to difficulty in VL treatment and control. Furthermore, VL treatment, which encompasses several problems including limited efficacy, emanation of drug-resistant parasites, exorbitant therapy, and exigency of hospitalization until the completion of treatment, further exacerbates disease severity. Therefore, there is an urgent need for the development of safe and efficacious therapies to control and eliminate this devastating disease. In such a scenario, biotherapy/immunotherapy against VL can become an alternative strategy with limited side effects and no or nominal chance of drug resistance. An extensive understanding of pathogenesis and immunological events that ensue during VL infection is vital for the development of immunotherapeutic strategies against VL. Immunotherapy alone or in combination with standard anti-leishmanial chemotherapeutic agents (immunochemotherapy) has shown better therapeutic outcomes in preclinical studies. This review extensively addresses VL treatment with an emphasis on immunotherapy or immunochemotherapeutic strategies to improve therapeutic outcomes as an alternative to conventional chemotherapy.
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Affiliation(s)
- Ganesh Yadagiri
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali, Punjab, India
- Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
| | - Aakriti Singh
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali, Punjab, India
| | - Kanika Arora
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali, Punjab, India
| | - Shyam Lal Mudavath
- Infectious Disease Biology Laboratory, Chemical Biology Unit, Institute of Nano Science and Technology, Mohali, Punjab, India
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14
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Furuta K, Onishi H, Ikada Y, Masaki K, Tanaka S, Kaito C. ATP and its metabolite adenosine cooperatively upregulate the antigen-presenting molecules on dendritic cells leading to IFN-γ production by T cells. J Biol Chem 2023; 299:104587. [PMID: 36889584 PMCID: PMC10124915 DOI: 10.1016/j.jbc.2023.104587] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 03/02/2023] [Accepted: 03/03/2023] [Indexed: 03/08/2023] Open
Abstract
Dendritic cells (DCs) present foreign antigens to T cells via the major histocompatibility complex (MHC), thereby inducing acquired immune responses. ATP accumulates at sites of inflammation or in tumor tissues, which triggers local inflammatory responses. However, it remains to be clarified how ATP modulates the functions of DCs. In this study, we investigated the effects of extracellular ATP on mouse bone marrow-derived dendritic cells (BMDCs), as well as the potential for subsequent T cell activation. We found that high concentrations of ATP (1 mM) upregulated the cell surface expression levels of MHC-I, MHC-II, and co-stimulatory molecules CD80 and CD86, but not those of co-inhibitory molecules PD-L1 and PD-L2 in BMDCs. Increased surface expression of MHC-I, MHC-II, CD80, and CD86 was inhibited by a pan-P2 receptor antagonist. In addition, the upregulation of MHC-I and MHC-II expression was inhibited by an adenosine P1 receptor antagonist and by inhibitors of CD39 and CD73, which metabolize ATP to adenosine. These results suggest that adenosine is required for the ATP-induced upregulation of MHC-I and MHC-II. In the mixed leukocyte reaction assay, ATP-stimulated BMDCs activated CD4 and CD8 T cells and induced interferon-gamma (IFN-γ) production by these T cells. Collectively, these results suggest that high concentrations of extracellular ATP upregulate the expression of antigen-presenting and co-stimulatory molecules but not that of co-inhibitory molecules in BMDCs. Cooperative stimulation of ATP and its metabolite adenosine was required for the upregulation of MHC-I and MHC-II. These ATP-stimulated BMDCs induced the activation of IFN-γ-producing T cells upon antigen presentation.
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Affiliation(s)
- Kazuyuki Furuta
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan.
| | - Hiroka Onishi
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
| | - Yuki Ikada
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
| | - Kento Masaki
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
| | - Satoshi Tanaka
- Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan
| | - Chikara Kaito
- Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
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15
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Li Y, Xiu Z, Li S, Zhu Y, Li Y, Zhao R, Li Y, Yang X, Ge C, Li N, Jin N, Shang C, Li X, Han J. Human adenovirus type 7 virus-like particle vaccine induces Dendritic cell maturation through the TLR4/NF-κB pathway and is highly immunogenic. Antiviral Res 2023; 212:105559. [PMID: 36813181 DOI: 10.1016/j.antiviral.2023.105559] [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: 12/09/2022] [Revised: 02/16/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023]
Abstract
Human adenovirus type 7 (HAdv-7) infection is the main cause of upper respiratory tract infection, bronchitis and pneumonia in children. At present, there are no anti-adenovirus drugs or preventive vaccines in the market. Therefore, it is necessary to develop a safe and effective anti-adenovirus type 7 vaccine. In this study, we designed a virus-like particle vaccine expressing the epitopes of hexon and penton of adenovirus type 7 with hepatitis B core protein (HBc) as the vector to induce high-level humoral and cellular immune responses. To evaluate the effectiveness of the vaccine, we first detected the expression of molecular markers on the surface of antigen presenting cells and the secretion of proinflammatory cytokines in vitro. We then measured the levels of neutralizing antibodies and T cell activation in vivo. The results showed that the HAdv-7 virus-like particles (VLPs) recombinant subunit vaccine could activate the innate immune response, including the TLR4/NF-κB pathway which upregulated the expression of MHC II, CD80, CD86, CD40 and cytokines. The vaccine also triggered a strong neutralizing antibody and cellular immune response and activated T lymphocytes. Therefore, the HAdv-7 VLPs promoted humoral and cellular immune responses, thereby potentially enhancing protection against HAdv-7 infection.
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Affiliation(s)
- Yiquan Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China; Medical College, Yanbian University, Yanji, 133002, PR China
| | - Zhiru Xiu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Shanzhi Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Yaru Li
- Medical College, Yanbian University, Yanji, 133002, PR China
| | - Renshuang Zhao
- Medical College, Yanbian University, Yanji, 133002, PR China
| | - Yue Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China
| | - Xia Yang
- Medical College, Yanbian University, Yanji, 133002, PR China
| | - Chenchen Ge
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China
| | - Nan Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China
| | - Ningyi Jin
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China; Medical College, Yanbian University, Yanji, 133002, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, 225009, PR China
| | - Chao Shang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China.
| | - Xiao Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China.
| | - Jicheng Han
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130117, PR China; Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130122, PR China.
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16
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Li Y, Yang X, Zhao R, Xiu Z, Li S, Li Y, Song G, Ge C, Fang J, Han J, Zhu Y, Li Y. Human adenovirus type 7 subunit vaccine induces dendritic cell maturation through the TLR4/NF-κB pathway is highly immunogenic. Front Cell Infect Microbiol 2023; 13:1117230. [PMID: 37124037 PMCID: PMC10130362 DOI: 10.3389/fcimb.2023.1117230] [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: 12/06/2022] [Accepted: 03/27/2023] [Indexed: 05/02/2023] Open
Abstract
Introduction Human adenovirus type 7 (HAdv-7) infection is the main cause of upper respiratory tract infection, bronchitis and pneumonia in children. At present, there are no anti- adenovirus drugs or preventive vaccines in the market. Therefore, it is necessary to develop a safe and effective anti-adenovirus type 7 vaccine. Methods In this study, In this study, we used the baculovirus-insect cell expression system to design a recombinant subunit vaccine expressing adenovirus type 7 hexon protein (rBV-hexon) to induce high-level humoral and cellular immune responses. To evaluate the effectiveness of the vaccine, we first detected the expression of molecular markers on the surface of antigen presenting cells and the secretion of proinflammatory cytokines in vitro. We then measured the levels of neutralizing antibodies and T cell activation in vivo. Results The results showed that the rBV-hexon recombinant subunit vaccine could promote DC maturation and improve its antigen uptake capability, including the TLR4/NF-κB pathway which upregulated the expression of MHCI, CD80, CD86 and cytokines. The vaccine also triggered a strong neutralizing antibody and cellular immune response, and activated T lymphocytes. Discussion Therefore, the recombinant subunit vaccine rBV-hexon promoted promotes humoral and cellular immune responses, thereby has the potential to become a vaccine against HAdv-7.
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Affiliation(s)
- Yaru Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
- Medical College, Yanbian University, Yanji, China
| | - Xia Yang
- Medical College, Yanbian University, Yanji, China
| | | | - Zhiru Xiu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
| | - Shanzhi Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
| | - Yue Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
| | - Gaojie Song
- Medical College, Jiujiang University, Jiujiang, China
| | - Chenchen Ge
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
| | - Jinbo Fang
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Yiquan Li, ; Yilong Zhu, ; Jicheng Han, ; Jinbo Fang,
| | - Jicheng Han
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Yiquan Li, ; Yilong Zhu, ; Jicheng Han, ; Jinbo Fang,
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Yiquan Li, ; Yilong Zhu, ; Jicheng Han, ; Jinbo Fang,
| | - Yiquan Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, China
- Medical College, Yanbian University, Yanji, China
- *Correspondence: Yiquan Li, ; Yilong Zhu, ; Jicheng Han, ; Jinbo Fang,
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17
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Parker H, Gravagnuolo AM, Vranic S, Crica LE, Newman L, Carnell O, Bussy C, Dookie RS, Prestat E, Haigh SJ, Lozano N, Kostarelos K, MacDonald AS. Graphene oxide modulates dendritic cell ability to promote T cell activation and cytokine production. NANOSCALE 2022; 14:17297-17314. [PMID: 36374249 DOI: 10.1039/d2nr02169b] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
An important aspect of immunotherapy is the ability of dendritic cells (DCs) to prime T cell immunity, an approach that has yielded promising results in some early phase clinical trials. However, novel approaches are required to improve DC therapeutic efficacy by enhancing their uptake of, and activation by, disease relevant antigens. The carbon nano-material graphene oxide (GO) may provide a unique way to deliver antigen to innate immune cells and modify their ability to initiate effective adaptive immune responses. We have assessed whether GO of various lateral sizes affects DC activation and function in vitro and in vivo, including their ability to take up, process and present the well-defined model antigen ovalbumin (OVA). We have found that GO flakes are internalised by DCs, while having minimal effect on their viability, activation phenotype or cytokine production. Although adsorption of OVA protein to either small or large GO flakes promoted its uptake into DCs, large GO interfered with OVA processing. In terms of modulation of DC function, delivery of OVA via small GO flakes significantly enhanced DC ability to induce proliferation of OVA-specific CD4+ T cells, promoting granzyme B secretion in vitro. On the other hand, delivery of OVA via large GO flakes augmented DC ability to induce proliferation of OVA-specific CD8+ T cells, and their production of IFN-γ and granzyme B. Together, these data demonstrate the capacity of GO of different lateral dimensions to act as a promising delivery platform for DC modulation of distinct facets of the adaptive immune response, information that could be exploited for future development of targeted immunotherapies.
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Affiliation(s)
- Helen Parker
- The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, UK.
| | - Alfredo Maria Gravagnuolo
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
| | - Sandra Vranic
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
| | - Livia Elena Crica
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
| | - Leon Newman
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
| | - Oliver Carnell
- The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, UK.
| | - Cyrill Bussy
- The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, UK.
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
| | - Rebecca S Dookie
- The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, UK.
| | - Eric Prestat
- School of Materials, University of Manchester, UK
- SuperSTEM Laboratory, SciTech Daresbury Campus, Daresbury, WA4 4AD, UK
| | - Sarah J Haigh
- National Graphene Institute, University of Manchester, UK
- School of Materials, University of Manchester, UK
| | - Neus Lozano
- Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain
| | - Kostas Kostarelos
- Nanomedicine Lab, University of Manchester, UK.
- National Graphene Institute, University of Manchester, UK
- Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, Bellaterra, 08193 Barcelona, Spain
| | - Andrew S MacDonald
- The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, UK.
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18
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Hamid B, Ebner F, Bechtold L, Kundik A, Rausch S, Hartmann S. Ascaris suum excretory/secretory products differentially modulate porcine dendritic cell subsets. Front Immunol 2022; 13:1012717. [DOI: 10.3389/fimmu.2022.1012717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
Abstract
Helminths produce excretory/secretory products (E/S) which can modulate the immune responses of their hosts. Dendritic cells (DC) are essential for initiating the host T cell response and are thus potential targets for modulation by helminth E/S. Here we study immunomodulation of porcine peripheral blood DC subsets following ex vivo stimulation with E/S from Ascaris suum, a common helminth of pigs with considerable public health and economic importance. Our data showed that the relative frequencies of DC subsets in porcine blood differ, with plasmacytoid DC (pDC) being the most prominent in healthy 6-month-old pigs. pDC are an important cytokine source, and we found that A. suum E/S suppressed production of the type 1 cytokines IL-12p40 and TNF-α by this subset following toll-like receptor (TLR) ligation. In contrast, conventional DC (cDC) are more efficient antigen presenters, and the expression of CD80/86, costimulatory molecules essential for efficient antigen presentation, were modulated differentially by A. suum E/S between cDC subsets. CD80/86 expression by type 1 cDC (cDC1) following TLR ligation was greatly suppressed by the addition of A. suum E/S, while CD80/86 expression by type 2 cDC (cDC2) was upregulated by A. suum E/S. Further, we found that IFN-γ production by natural killer (NK) cells following IL-12 and IL-18 stimulation was suppressed by A. suum E/S. Finally, in the presence of E/S, IFN-γ production by CD4+ T cells co-cultured with autologous blood-derived DC was significantly impaired. Together, these data provide a coherent picture regarding the regulation of type 1 responses by A. suum E/S. Responsiveness of pDC and cDC1 to microbial ligands is reduced in the presence of E/S, effector functions of Th1 cells are impaired, and cytokine-driven IFN-γ release by NK cells is limited.
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Jiang S, Nan F, Zhang S, Zhang X, Li Z, Yu Z, Liu F, Li J, Zhou X, Niu D, Wang H, Zhang X, Liu W, Yang X, Wang Y, Wang B. CRM197-conjugated multi antigen dominant epitope for effective human cytomegalovirus vaccine development. Int J Biol Macromol 2022; 224:79-93. [DOI: 10.1016/j.ijbiomac.2022.10.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/11/2022] [Accepted: 10/11/2022] [Indexed: 11/05/2022]
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20
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Li LX, Feng X, Tao MT, Paulsen BS, Huang C, Feng B, Liu W, Yin ZQ, Song X, Zhao X, Liang XX, Yin LZ, Tang HQ, Zou YF. Benefits of neutral polysaccharide from rhizomes of Polygonatum sibiricum to intestinal function of aged mice. Front Nutr 2022; 9:992102. [PMID: 36204377 PMCID: PMC9531825 DOI: 10.3389/fnut.2022.992102] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/30/2022] [Indexed: 11/22/2022] Open
Abstract
One purified neutral polysaccharide fraction was obtained from the rhizome of Polygonatum sibiricum by DEAE ion exchange and gel chromatography. Structure elucidation was performed by methanolysis, methylation, FT-IR, and NMR. The results indicated that PSP-NP was composed of 1,4-β-D-Gal,1, 4, 6-β-D-Gal, T-α-D-Man,1, 4-α-D-Glc, and T-α-D-Glc with a molecular weight of 43.0 kDa. We supplied this polysaccharide to aged mice and found it is of benefits to intestinal functions, as indicated by better tissue integrity and motility, improved oxidative stress and inflammation, reduced intestinal permeability and serum LPS level, as well as balanced gut microbial composition and short-chain fatty acids production. These results display a novel Polygonatum sibiricum polysaccharide to improve the intestinal function of aged mice, which provides pieces of evidence for its further development and utilization.
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Affiliation(s)
- Li-Xia Li
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xin Feng
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Meng-Ting Tao
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Berit Smestad Paulsen
- Department of Pharmacy, Section Pharmaceutical Chemistry, Area Pharmacognosy, University of Oslo, Oslo, Norway
| | - Chao Huang
- Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Bin Feng
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, China
| | - Wei Liu
- Key Laboratory of the Ministry of Education for the Standardization of Traditional Chinese Medicine, Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhong-Qiong Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xu Song
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xinghong Zhao
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Xiao-Xia Liang
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Li-Zi Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Hua-Qiao Tang
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Yuan-Feng Zou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
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21
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Upconversion nanoparticle platform for efficient dendritic cell antigen delivery and simultaneous tracking. Mikrochim Acta 2022; 189:368. [PMID: 36057018 PMCID: PMC9440881 DOI: 10.1007/s00604-022-05441-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/31/2022] [Indexed: 11/10/2022]
Abstract
Upconversion nanoparticles (UCNPs) represent a group of NPs that can convert near-infrared (NIR) light into ultraviolet and visible light, thus possess deep tissue penetration power with less background fluorescence noise interference, and do not induce damage to biological tissues. Due to their unique optical properties and possibility for surface modification, UCNPs can be exploited for concomitant antigen delivery into dendritic cells (DCs) and monitoring by molecular imaging. In this study, we focus on the development of a nano-delivery platform targeting DCs for immunotherapy and simultaneous imaging. OVA 254–267 (OVA24) peptide antigen, harboring a CD8 T cell epitope, and Pam3CysSerLys4 (Pam3CSK4) adjuvant were chemically linked to the surface of UCNPs by amide condensation to stimulate DC maturation and antigen presentation. The OVA24-Pam3CSK4-UCNPs were thoroughly characterized and showed a homogeneous morphology and surface electronegativity, which promoted a good dispersion of the NPs. In vitro experiments demonstrated that OVA24-Pam3CSK4-UCNPs induced a strong immune response, including DC maturation, T cell activation, and proliferation, as well as interferon gamma (IFN-γ) production. In vivo, highly sensitive upconversion luminescence (UCL) imaging of OVA24-Pam3CSK4-UCNPs allowed tracking of UCNPs from the periphery to lymph nodes. In summary, OVA24-Pam3CSK4-UCNPs represent an effective tool for DC-based immunotherapy.
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22
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Tsubokura Y, Yoshimura H, Satake A, Nasa Y, Tsuji R, Ito T, Nomura S. Early administration of lenalidomide after allogeneic hematopoietic stem cell transplantation suppresses graft-versus-host disease by inhibiting T-cell migration to the gastrointestinal tract. Immun Inflamm Dis 2022; 10:e688. [PMID: 36039651 PMCID: PMC9425011 DOI: 10.1002/iid3.688] [Citation(s) in RCA: 3] [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: 02/18/2022] [Revised: 07/30/2022] [Accepted: 08/01/2022] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment for hematopoietic malignancies. Graft-versus-host disease (GVHD) is a major complication of aHSCT. After transplantation, the balance of immune conditions, such as proinflammatory cytokine level and T-cell subset count, influences GVHD magnitude. Lenalidomide (LEN) is an immunomodulatory drug used for treating several hematological malignancies such as multiple myeloma, adult T-cell lymphoma/leukemia, and follicular lymphoma. However, the impact of LEN on immune responses after aHSCT has not been elucidated. METHODS We analyzed the lymphocyte composition in naïve mice treated with LEN. Subsequently, we treated host mice with LEN, soon after aHSCT, and analyzed GVHD severity as well as the composition and characteristics of lymphocytes associated with GVHD. RESULTS Using a mouse model, we demonstrated the beneficial effects of LEN for treating acute GVHD. Although natural killer cells were slightly increased by LEN, it did not significantly change T-cell proliferation and the balance of the T-cell subset in naïve mice. LEN did not modulate the suppressive function of regulatory T cells (Tregs). Unexpectedly, LEN prevented severe GVHD in a mouse acute GVHD model. Donor-derived lymphocytes were more numerous in host mice treated with LEN than in host mice treated with vehicle. Lymphocyte infiltration of the gastrointestinal tract in host mice treated with LEN was less severe compared to that in host mice treated with vehicle. The percentage of LPAM-1 (α4 β7 -integrin)-expressing Foxp3- CD4+ T cells was significantly lower in host mice treated with LEN than in host mice treated with vehicle, whereas that of LPAM-1-expressing Tregs was comparable. CONCLUSIONS LEN may be useful as a prophylactic agent for acute GVHD-induced mortality through the inhibition of lymphocyte migration to the gastrointestinal tract. Our data show the effect of LEN on immune responses early after aHSCT and suggest that cereblon, a molecular target of LEN, may be a therapeutic target for preventing acute GVHD-induced mortality.
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Affiliation(s)
- Yukie Tsubokura
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Hideaki Yoshimura
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Atsushi Satake
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Yutaro Nasa
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Ryohei Tsuji
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Tomoki Ito
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
| | - Shosaku Nomura
- First Department of Internal MedicineKansai Medical UniversityHirakata CityOsakaJapan
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23
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Stunnenberg M, van Hamme JL, Zijlstra‐Willems EM, Gringhuis SI, Geijtenbeek TB. Crosstalk between R848 and abortive HIV-1 RNA-induced signaling enhances antiviral immunity. J Leukoc Biol 2022; 112:289-298. [PMID: 34982481 PMCID: PMC9542596 DOI: 10.1002/jlb.4a0721-365r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Pathogens trigger multiple pattern recognition receptors (PRRs) that together dictate innate and adaptive immune responses. Understanding the crosstalk between PRRs is important to enhance vaccine efficacy. Abortive HIV-1 RNA transcripts are produced during acute and chronic HIV-1 infection and are known ligands for different PRRs, leading to antiviral and proinflammatory responses. Here, we have investigated the crosstalk between responses induced by these 58 nucleotide-long HIV-1 RNA transcripts and different TLR ligands. Costimulation of dendritic cells (DCs) with abortive HIV-1 RNA and TLR7/8 agonist R848, but not other TLR agonists, resulted in enhanced antiviral type I IFN responses as well as adaptive immune responses via the induction of DC-mediated T helper 1 (TH 1) responses and IFNγ+ CD8+ T cells. Our data underscore the importance of crosstalk between abortive HIV-1 RNA and R848-induced signaling for the induction of effective antiviral immunity.
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Affiliation(s)
- Melissa Stunnenberg
- Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Amsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - John L. van Hamme
- Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Amsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Esther M. Zijlstra‐Willems
- Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Amsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Sonja I. Gringhuis
- Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Amsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
| | - Teunis B.H. Geijtenbeek
- Department of Experimental Immunology, Amsterdam institute for Infection & Immunity, Amsterdam UMC, University of AmsterdamAmsterdamThe Netherlands
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24
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Han M, Ma J, Ouyang S, Wang Y, Zheng T, Lu P, Zheng Z, Zhao W, Li H, Wu Y, Zhang B, Hu R, Otsu K, Liu X, Wan Y, Li H, Huang G. The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation. Cell Mol Immunol 2022; 19:805-819. [PMID: 35551270 PMCID: PMC9243149 DOI: 10.1038/s41423-022-00873-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 04/02/2022] [Accepted: 04/15/2022] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.
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Affiliation(s)
- Miaomiao Han
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China
| | - Jingyu Ma
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Suidong Ouyang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Yanyan Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Tingting Zheng
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Peishan Lu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Zihan Zheng
- Biomedical Analysis Center, Army Medical University, 400038, Chongqing, China
| | - Weiheng Zhao
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.,Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China
| | - Hongjin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.,Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 200437, Shanghai, China
| | - Yun Wu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Baohua Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.,Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China
| | - Ran Hu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.,Basic Department of Cancer Center, Shanghai Tenth People's Hospital of Tongji University, 200072, Shanghai, China
| | - Kinya Otsu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.,School of Cardiovascular Medicine and Sciences, King's College London, London, SE59NU, UK
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China
| | - Ying Wan
- Biomedical Analysis Center, Army Medical University, 400038, Chongqing, China.
| | - Huabin Li
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 200031, Shanghai, China.
| | - Gonghua Huang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China. .,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, 523808, Dongguan, China.
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25
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Koido S, Horiuchi S, Kan S, Bito T, Ito Z, Uchiyama K, Saruta M, Sato N, Ohkusa T. The stimulatory effect of fusobacteria on dendritic cells under aerobic or anaerobic conditions. Sci Rep 2022; 12:10698. [PMID: 35739324 PMCID: PMC9225986 DOI: 10.1038/s41598-022-14934-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 06/15/2022] [Indexed: 11/16/2022] Open
Abstract
Fusobacteria have been suspected to be pathobionts of colon cancer and inflammatory bowel disease. However, the immunomodulatory properties that affect these inflammatory reactions in dendritic cells (DCs) under anaerobic and aerobic conditions have not yet been characterized. We directly assessed the stimulatory effects of anaerobic commensal bacteria, including fusobacteria, on a human DC line through coculture under aerobic or anaerobic conditions. Under aerobic or anaerobic conditions, stimulation of the DC line with all live commensal bacteria examined, except the probiotic Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus), significantly increased the geometric mean fluorescent intensity (MFI) of marker proteins (HLA-ABC, HLA-DR, CD80, CD86, CD83, or CCR7) on the DC surface. In particular, both Fusobacterium nucleatum (F. nucleatum) and Escherichia coli (E. coli) significantly increased the expression of DC-associated molecules, except for CD83 under both aerobic and anaerobic conditions. The DC line stimulated with Fusobacterium varium (F. varium) significantly increased only CD80, HLA-ABC, and HLA-DR expression under anaerobic conditions. Moreover, differences in the levels of proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, were detected in the DC line stimulated by all live commensal bacteria under either aerobic or anaerobic conditions. Under aerobic conditions, the DC line stimulated with E. coli produced significantly more IL-6, IL-8, and TNF-α than did the cells stimulated with any of the bacteria examined. When E. coli were used to stimulate the DC line under anaerobic conditions, TNF-α was predominantly produced compared to stimulation with any other bacteria. Compared to the DC line stimulated with any other bacteria, the cells stimulated with F. nucleatum showed significantly increased production of IL-6, IL-8 and TNF-α only under anaerobic conditions. In particular, E. coli, F. nucleatum, and F. varium strongly stimulated the DC line, resulting in significantly increased expression of surface molecules associated with DCs and production of inflammatory cytokines.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan.
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan.
| | - Sankichi Horiuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Shin Kan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Tsuuse Bito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
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26
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dos Santos JDMB, do Amaral JB, França CN, Monteiro FR, Alvares-Saraiva AM, Kalil S, Durigon EL, Oliveira DBL, Rodrigues SS, Heller D, Welter EAR, Pinho JRR, Vieira RP, Bachi ALL. Distinct Immunological Profiles Help in the Maintenance of Salivary Secretory IgA Production in Mild Symptoms COVID-19 Patients. Front Immunol 2022; 13:890887. [PMID: 35686128 PMCID: PMC9171398 DOI: 10.3389/fimmu.2022.890887] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Relevant aspects regarding the SARS-CoV-2 pathogenesis and the systemic immune response to this infection have been reported. However, the mucosal immune response of the upper airways two months after SARS-CoV-2 infection in patients with mild/moderate symptoms is still not completely described. Therefore, we investigated the immune/inflammatory responses of the mucosa of the upper airways of mild/moderate symptom COVID-19 patients two months after the SARS-CoV-2 infection in comparison to a control group composed of non-COVID-19 healthy individuals. METHODS A cohort of 80 volunteers (age 37.2 ± 8.2), including non-COVID-19 healthy individuals (n=24) and COVID-19 patients (n=56) who presented mild/moderate symptoms during a COVID-19 outbreak in Brazil in November and December of 2020. Saliva samples were obtained two months after the COVID-19 diagnosis to assess the levels of SIgA by ELISA and the cytokines by multiplex analysis. RESULTS Salivary levels of SIgA were detected in 39 volunteers into the COVID-19 group and, unexpectedly, in 14 volunteers in the control group. Based on this observation, we distributed the volunteers of the control group into without SIgA or with SIgA sub-groups, and COVID-19 group into without SIgA or with SIgA sub-groups. Individuals with SIgA showed higher levels of IL-10, IL-17A, IFN-γ, IL-12p70, IL-13, and IFN-α than those without SIgA. In intergroup analysis, the COVID-19 groups showed higher salivary levels of IL-10, IL-13, IL-17A, and IFN-α than the control group. No statistical differences were verified in the salivary levels of IL-6 and IFN-β. Lower IL-12p70/IL-10 and IFN-γ/IL-10 ratios were found in the control group without SIgA than the control group with SIgA and the COVID-19 group with SIgA. CONCLUSION We were able to present, for the first time, that associations between distinct immunological profiles can help the mucosal immunity to maintain the salivary levels of SIgA in COVID-19 patients two months after the SARS-CoV-2 infection.
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Affiliation(s)
| | - Jonatas Bussador do Amaral
- ENT Research Lab, Department of Otorhinolaryngology –Head and Neck Surgery, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil
| | - Carolina Nunes França
- Post-Graduation Program in Health Sciences, Santo Amaro University (UNISA), São Paulo, Brazil
| | | | | | - Sandra Kalil
- Programa de Pós-Graduação em Patologia Ambiental e Experimental, Universidade Paulista - Unip, São Paulo, Brazil
| | - Edison Luiz Durigon
- Laboratory of Clinical and Molecular Virology, Department of Microbiology, Institute of Biomedical Science of the University of São Paulo, São Paulo, Brazil
- Scientific Platform Pasteur, University of São Paulo, São Paulo, Brazil
| | - Danielle Bruna Leal Oliveira
- Laboratory of Clinical and Molecular Virology, Department of Microbiology, Institute of Biomedical Science of the University of São Paulo, São Paulo, Brazil
- Albert Einstein Institute for Teaching and Research (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Silvia Sanches Rodrigues
- Albert Einstein Institute for Teaching and Research (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Debora Heller
- Albert Einstein Institute for Teaching and Research (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil
- Post Graduate Program in Dentistry, Universidade Cruzeiro Do Sul, São Paulo, Brazil
- Department of Periodontology, School of Dentistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | | | - João Renato Rebello Pinho
- Albert Einstein Institute for Teaching and Research (IIEP), Hospital Israelita Albert Einstein, São Paulo, Brazil
- Department of Gastroenterology (LIM07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Division of Clinical Laboratories (LIM 03), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Rodolfo P. Vieira
- Post-Graduation Program in Science of Human and Rehabilitation, Federal University of São Paulo (UNIFESP), Santos, Brazil
- Post-Graduation Program in Human Movement and Rehabilitation, Unievangélica, Anápolis, Brazil
- Post-Graduation Program in Bioengineering, Universidade Brasil, São Paulo, Brazil
| | - André Luis Lacerda Bachi
- ENT Research Lab, Department of Otorhinolaryngology –Head and Neck Surgery, Federal University of Sao Paulo (UNIFESP), São Paulo, Brazil
- Post-Graduation Program in Health Sciences, Santo Amaro University (UNISA), São Paulo, Brazil
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27
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Lin H, Peng S, Guo S, Ma B, Lucherelli MA, Royer C, Ippolito S, Samorì P, Bianco A. 2D Materials and Primary Human Dendritic Cells: A Comparative Cytotoxicity Study. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2107652. [PMID: 35451183 DOI: 10.1002/smll.202107652] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/24/2022] [Indexed: 06/14/2023]
Abstract
Human health can be affected by materials indirectly through exposure to the environment or directly through close contact and uptake. With the ever-growing use of 2D materials in many applications such as electronics, medical therapeutics, molecular sensing, and energy storage, it has become more pertinent to investigate their impact on the immune system. Dendritic cells (DCs) are highly important, considering their role as the main link between the innate and the adaptive immune system. By using primary human DCs, it is shown that hexagonal boron nitride (hBN), graphene oxide (GO) and molybdenum disulphide have minimal effects on viability. In particular, it is evidenced that hBN and GO increase DC maturation, while GO leads to the release of reactive oxygen species and pro-inflammatory cytokines. hBN and MoS2 increase T cell proliferation with and without the presence of DCs. hBN in particular does not show any sign of downstream T cell polarization. The study allows ranking of the three materials in terms of inherent toxicity, providing the following trend: GO > hBN ≈ MoS2 , with GO the most cytotoxic.
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Affiliation(s)
- Hazel Lin
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Shiyuan Peng
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Shi Guo
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Baojin Ma
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Matteo Andrea Lucherelli
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
| | - Cathy Royer
- Plateforme Imagerie In Vitro de l'ITI Neurostra, CNRS UAR 3156, University of Strasbourg, Strasbourg, 67000, France
| | | | - Paolo Samorì
- CNRS, ISIS, Université de Strasbourg, Strasbourg, 67000, France
| | - Alberto Bianco
- CNRS, Immunology, Immunopathology and Therapeutic Chemistry UPR 3572, University of Strasbourg, ISIS, Strasbourg, 67000, France
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28
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Hopkins GV, Cochrane S, Onion D, Fairclough LC. The Role of Lipids in Allergic Sensitization: A Systematic Review. Front Mol Biosci 2022; 9:832330. [PMID: 35495627 PMCID: PMC9047936 DOI: 10.3389/fmolb.2022.832330] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Immunoglobulin E (IgE)-mediated allergies are increasing in prevalence, with IgE-mediated food allergies currently affecting up to 10% of children and 6% of adults worldwide. The mechanisms underpinning the first phase of IgE-mediated allergy, allergic sensitization, are still not clear. Recently, the potential involvement of lipids in allergic sensitization has been proposed, with reports that they can bind allergenic proteins and act on immune cells to skew to a T helper type 2 (Th2) response. Objectives: The objective of this systematic review is to determine if there is strong evidence for the role of lipids in allergic sensitization. Methods: Nineteen studies were reviewed, ten of which were relevant to lipids in allergic sensitization to food allergens, nine relevant to lipids in aeroallergen sensitization. Results: The results provide strong evidence for the role of lipids in allergies. Intrinsic lipids from allergen sources can interact with allergenic proteins to predominantly enhance but also inhibit allergic sensitization through various mechanisms. Proposed mechanisms included reducing the gastrointestinal degradation of allergenic proteins by altering protein structure, reducing dendritic cell (DC) uptake of allergenic proteins to reduce immune tolerance, regulating Th2 cytokines, activating invariant natural killer T (iNKT) cells through CD1d presentation, and directly acting upon toll-like receptors (TLRs), epithelial cells, keratinocytes, and DCs. Conclusion: The current literature suggests intrinsic lipids are key influencers of allergic sensitization. Further research utilising human relevant in vitro models and clinical studies are needed to give a reliable account of the role of lipids in allergic sensitization.
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Affiliation(s)
- Georgina V. Hopkins
- School of Life Sciences, The University of Nottingham, Nottingham, United Kingdom
| | - Stella Cochrane
- SEAC, Unilever, Colworth Science Park, Sharnbrook, United Kingdom
| | - David Onion
- School of Life Sciences, The University of Nottingham, Nottingham, United Kingdom
| | - Lucy C. Fairclough
- School of Life Sciences, The University of Nottingham, Nottingham, United Kingdom
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Lee DH, Park HK, Lee HR, Sohn H, Sim S, Park HJ, Shin YS, Kim YK, Choi Y, Park HS. Immunoregulatory effects of Lactococcus lactis-derived extracellular vesicles in allergic asthma. Clin Transl Allergy 2022; 12:e12138. [PMID: 35344296 PMCID: PMC8967260 DOI: 10.1002/clt2.12138] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/23/2022] [Accepted: 03/11/2022] [Indexed: 11/12/2022] Open
Abstract
Background Probiotics have been shown to prevent various allergic diseases by producing extracellular vesicles (EVs). However, the role of EVs in allergic asthma has not yet been completely determined. Methods Gut microbial composition, mainly genera related to probiotics, was investigated in allergic asthmatic mice. Moreover, EVs were isolated from Lactococcus lactis (L. lactis, a selected bacterium) and EV proteins were identified by peptide mass fingerprinting. EV functions in immune responses were evaluated in vivo or ex vivo. Furthermore, the levels of specific IgG antibodies (an alternative marker for EV quantification) to L. lactis‐EVs were measured by ELISA in the sera of 27 asthmatic patients and 26 healthy controls. Results Allergic asthmatic mice showed a lower proportion of Lactococcus compared to healthy mice. L. lactis was cultured and its EVs abundantly contained pyruvate kinase. When allergic asthmatic mice were intranasally treated with EVs, airway hyperresponsiveness, eosinophil number, cytokine secretion, and mucus production were significantly decreased. Moreover, L. lactis‐EV treatment shifted immune responses from Th2 to Th1 by stimulating dendritic cells to produce IL‐12. In addition, significantly lower levels of serum specific IgG4 (but not IgG1) to L. lactis‐EVs were noted in asthmatic patients than in healthy controls. A positive correlation between the levels of EV‐specific IgG4 and FEV1 (%), but a negative correlation between the levels of EV‐specific IgG4 and IL‐13 were observed. Conclusion These findings suggest that L. lactis‐EVs may have immune‐regulating effects on airway inflammation mediated by dendritic cell activation, providing a potential benefit for allergic asthma.
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Affiliation(s)
- Dong-Hyun Lee
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Han-Ki Park
- Department of Allergy and Clinical Immunology, School of Medicine, Kyungpook National University, Daegu, Korea
| | | | - Hyeukjun Sohn
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Soyoon Sim
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | | | - Yoo Seob Shin
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | | | - Youngwoo Choi
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
| | - Hae-Sim Park
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
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Nabeel MM, Darwish RK, Alakel W, Maher R, Mostafa H, Hashem A, Elbeshlawy M, Abul-Fotouh A, Shousha HI, Saeed Marie M. Changes in Serum Interferon Gamma and Interleukin-10 in Relation to Direct-Acting Antiviral Therapy of Chronic Hepatitis C Genotype 4: A Pilot Study. J Clin Exp Hepatol 2022; 12:428-434. [PMID: 35535108 PMCID: PMC9077187 DOI: 10.1016/j.jceh.2021.06.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 06/19/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION This study analyzes the changing levels of circulating inflammatory cytokines Interferon gamma (IFN-γ) and interleukin (IL)-10 (as the main cytokines of T-helper-1 and T-helper-2 immune responses) in patients with chronic hepatitis C virus (HCV) infection undergoing therapy with direct-acting antivirals (DAAs) and to correlate them with laboratory markers. METHODS This Pilot study included 50 HCV monoinfected patients who received DAAs for 12 or 24 weeks. They were followed up monthly during therapy and 3 months after the end of the treatment. Liver disease was determined by transient elastography, in addition to FIB-4 indices. Analysis of IFN-gamma and IL-10 was carried out using an enzyme-linked immunosorbent assay. RESULTS All patients carried HCV genotype 4. The Sustained virological response was 100% and 92% in cirrhotics and noncirrhotics, respectively. There was no significant difference between groups in baseline IL-10 or IFN-gamma. In noncirrhotics, IL-10 showed a significant reduction at Week 4 after treatment start. In cirrhotics, IL-10 showed a significant reduction at Week 4 after treatment starts and a significant reduction at Week 12 after the end of the treatment. At Week 12 after the end of the treatment, serum IL-10 levels were significantly lower in cirrhotics. IFN-γ showed nonsignificant changes in noncirrhotics. A significant increase of IFN-γ occurred in cirrhotics from Week 4 after treatment starts to 12 weeks after the end of the treatment. IFN-γ was significantly higher in cirrhotics at Week 12 after the end of the treatment. IFN-γ and IL-10 showed different correlations with laboratory markers. CONCLUSION Viral eradication induced by DAAs caused a significant change in IL-10 and IFN-gamma.
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Key Words
- ALT, alanine transaminase
- AST, aspartate transaminase
- CHC, chronic hepatitis c
- DAA, Direct-acting antivirals
- DAC, daclatasvir
- DM, diabetes melliteus
- EDTA, ethylenediaminetetraacetic acid
- HCV, Hepatitis C virus
- HTN, systemic hypertension
- IFN-γ, interferon gamma
- IL-10, interleukin 10
- INR, international normalized ratio
- NCCVH, National Committee for Control of Viral Hepatitis
- SOF, sofosbuvir
- STROBE, strengthening the reporting of observational studies in epidemiology
- SVR, sustained virological response rates
- Th, T-helper
- cytokines
- direct-acting antivirals
- hepatitis C virus
- interferon gamma
- interleukin-10
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Affiliation(s)
- Mohamed M. Nabeel
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rania K. Darwish
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wafaa Alakel
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rabab Maher
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hossam Mostafa
- Internal Medicine and Hepatogastroenterology, Students' Hospital, Cairo University, Cairo, Egypt
| | - Ahmed Hashem
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Elbeshlawy
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Amr Abul-Fotouh
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend I. Shousha
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamad Saeed Marie
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Wu R, Yuan X, Li X, Ma N, Jiang H, Tang H, Xu G, Liu Z, Zhang Z. The bile acid-activated retinoic acid response in dendritic cells is involved in food allergen sensitization. Allergy 2022; 77:483-498. [PMID: 34365653 DOI: 10.1111/all.15039] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 06/13/2021] [Accepted: 06/27/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Alteration of commensal microbiota is highly correlated with the prevalence of allergic reactions to food in the gastrointestinal tract. The mechanisms by which microbiota modulate food allergen sensitization in the mucosal site are not fully understood. METHODS We generate DCs specific knockout of retinoic acid receptor α (Rara) gene mice (DC KO Rara) to evaluate food sensitization. The bile acid-activated retinoic acid response was evaluated by flow cytometry, real-time RT-PCR and Illumina transcriptome sequencing. The global effect of Abx treatment on BA profiles in the mucosal lymph tissue mLN in mice was examined by UPLC-MS analysis. RESULTS In this study, we demonstrate that depletion of commensal gut bacteria leads to enhanced retinoic acid (RA) signaling in mucosal dendritic cells (DCs). RA signaling in DCs is required for the production of food allergen-specific IgE and IgG1. Antibiotics induced an enlarged bile acid (BA) pool, and dysregulated BA profiles contributed to enhanced RA signaling in mucosal DCs. BA-activated RA signaling promoted DC upregulation of interferon I signature, RA signature, OX40L, and PDL2, which may lead to T helper 2 differentiation of CD4+ T cells. BA-activated RA signaling involved the farnesoid X receptor and RA receptor α (RARa) interaction. Depletion of bile acid reduces food allergen specific IgE and IgG1 levels in mice. CONCLUSION Our research unveils a mechanism of food sensitization modulated by BA-RA signaling in DCs, which suggests a potential new approach for the intervention of food allergic reactions.
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Affiliation(s)
- Renlan Wu
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
- Model Animal Research Center Nanjing University Nanjing China
| | - Xiefang Yuan
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
| | - Xingjie Li
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
- The School of Basic Medical Sciences Southwest Medical University Sichuan China
| | - Ning Ma
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
| | - Hongyu Jiang
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
- The School of Basic Medical Sciences Southwest Medical University Sichuan China
| | - Hongmei Tang
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
| | - Guofeng Xu
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
| | - Zhigang Liu
- State Key Laboratory of Respiratory Disease for Allergy at Shenzhen UniversityShenzhen University School of Medicine Shenzhen China
| | - Zongde Zhang
- Inflammation & Allergic Diseases Research Unit Affiliated Hospital of Southwest Medical University Sichuan China
- The School of Basic Medical Sciences Southwest Medical University Sichuan China
- Model Animal Research Center Nanjing University Nanjing China
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Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity. Int J Mol Sci 2022; 23:ijms23031104. [PMID: 35163028 PMCID: PMC8834748 DOI: 10.3390/ijms23031104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/16/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023] Open
Abstract
While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.
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Askoura M, Abbas HA, Al Sadoun H, Abdulaal WH, Abu Lila AS, Almansour K, Alshammari F, Khafagy ES, Ibrahim TS, Hegazy WAH. Elevated Levels of IL-33, IL-17 and IL-25 Indicate the Progression from Chronicity to Hepatocellular Carcinoma in Hepatitis C Virus Patients. Pathogens 2022; 11:pathogens11010057. [PMID: 35056005 PMCID: PMC8781674 DOI: 10.3390/pathogens11010057] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/09/2021] [Accepted: 01/01/2022] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) is one of the most epidemic viral infections in the world. Three-quarters of individuals infected with HCV become chronic. As a consequence of persistent inflammation, a considerable percentage of chronic patients progress to liver fibrosis, cirrhosis, and finally hepatocellular carcinoma. Cytokines, which are particularly produced from T-helper cells, play a crucial role in immune protection against HCV and the progression of the disease as well. In this study, the role of interleukins IL-33, IL-17, and IL-25 in HCV patients and progression of disease from chronicity to hepatocellular carcinoma will be characterized in order to use them as biomarkers of disease progression. The serum levels of the tested interleukins were measured in patients suffering from chronic hepatitis C (CHC), hepatocellular carcinoma (HCC), and healthy controls (C), and their levels were correlated to the degree of liver fibrosis, liver fibrosis markers and viral load. In contrast to the IL-25 serum level, which increased in patients suffering from HCC only, the serum levels of both IL-33 and IL-17 increased significantly in those patients suffering from CHC and HCC. In addition, IL-33 serum level was found to increase by liver fibrosis progression and viral load, in contrast to both IL-17 and IL-25. Current results indicate a significant role of IL-33 in liver inflammation and fibrosis progress in CHC, whereas IL-17 and IL-25 may be used as biomarkers for the development of hepatocellular carcinoma.
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Affiliation(s)
- Momen Askoura
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
- Correspondence: (M.A.); (W.A.H.H.); Tel.: +20-1125226642 (M.A.); +20-1101188800 (W.A.H.H.)
| | - Hisham A. Abbas
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
| | - Hadeel Al Sadoun
- King Fahd Medical Research Center, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Wesam H. Abdulaal
- Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Amr S. Abu Lila
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia; (A.S.A.L.); (K.A.); (F.A.)
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Khaled Almansour
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia; (A.S.A.L.); (K.A.); (F.A.)
| | - Farhan Alshammari
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia; (A.S.A.L.); (K.A.); (F.A.)
| | - El-Sayed Khafagy
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Suez Canal University, Ismailia 41552, Egypt
| | - Tarek S. Ibrahim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
| | - Wael A. H. Hegazy
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt;
- Correspondence: (M.A.); (W.A.H.H.); Tel.: +20-1125226642 (M.A.); +20-1101188800 (W.A.H.H.)
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Wu J, Yang H, Xu JC, Hu Z, Gu WF, Chen ZY, Xia JX, Lowrie DB, Lu SH, Fan XY. Mycobacterium tuberculosis Rv3628 isan effective adjuvant via activationof dendritic cells for cancer immunotherapy. MOLECULAR THERAPY-ONCOLYTICS 2021; 23:288-302. [PMID: 34786473 PMCID: PMC8571481 DOI: 10.1016/j.omto.2021.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/24/2021] [Accepted: 10/07/2021] [Indexed: 12/30/2022]
Abstract
Tumor antigens (Ags) are weakly immunogenic and elicit inadequate immune responses, thus induction of antigen-specific immune activation via the maturation of dendritic cells (DCs) is a strategy used for cancer immunotherapy. In this study, we examined the effect of Rv3628 from Mycobacterium tuberculosis (Mtb) on activation of DCs and anti-tumor immunity in vivo. Intravenous injection of mice with Rv3628 promoted DC activation of spleen and lymph nodes. More importantly, Rv3628 also induced activation of DCs and enhanced Ag presentation in tumor-bearing mice. In mice bearing ovalbumin (OVA)-expressing tumors, combination treatment with Rv3628 and OVA peptide promoted OVA-specific T cell activation and accumulation of interferon (IFN)-γ and tumor necrosis factor (TNF)-α-producing OT-I and OT-II cells in tumor-draining lymph nodes. Moreover, three different tumor Ags in three different tumor models showed enhanced anti-tumor activity with Rv3628 as adjuvant, including inhibition of growth of OVA-expressing B16 melanoma, CT26 carcinoma, and B16 melanoma tumors, and a synergistic effect with anti-programmed cell death protein 1 (PD-1) antibody treatment. Additionally, potential application against human tumors was indicated by similar activation of human peripheral blood DCs by Rv3628. Taken together, these data demonstrate that Rv3628 could be an effective adjuvant in tumor immunotherapy via enhanced capacity of DC activation and Ag presentation.
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Affiliation(s)
- Juan Wu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China.,TB Center, Shanghai Emerging and Re-emerging Infectious Disease Institute, Fudan University, Shanghai 201508, China
| | - Heng Yang
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China
| | - Jin-Chuan Xu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China
| | - Zhidong Hu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China.,TB Center, Shanghai Emerging and Re-emerging Infectious Disease Institute, Fudan University, Shanghai 201508, China
| | - Wen-Fei Gu
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, China
| | - Zhen-Yan Chen
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China
| | - Jing-Xian Xia
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China
| | - Douglas B Lowrie
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China
| | - Shui-Hua Lu
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China.,TB Center, Shanghai Emerging and Re-emerging Infectious Disease Institute, Fudan University, Shanghai 201508, China
| | - Xiao-Yong Fan
- Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 201508, China.,TB Center, Shanghai Emerging and Re-emerging Infectious Disease Institute, Fudan University, Shanghai 201508, China.,School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, China
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Sarkar MH, Yagi R, Endo Y, Koyama-Nasu R, Wang Y, Hasegawa I, Ito T, Junttila IS, Zhu J, Kimura MY, Nakayama T. IFNγ suppresses the expression of GFI1 and thereby inhibits Th2 cell proliferation. PLoS One 2021; 16:e0260204. [PMID: 34807911 PMCID: PMC8608330 DOI: 10.1371/journal.pone.0260204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 11/04/2021] [Indexed: 11/23/2022] Open
Abstract
While IFNγ is a well-known cytokine that actively promotes the type I immune response, it is also known to suppress the type II response by inhibiting the differentiation and proliferation of Th2 cells. However, the mechanism by which IFNγ suppresses Th2 cell proliferation is still not fully understood. We found that IFNγ decreases the expression of growth factor independent-1 transcriptional repressor (GFI1) in Th2 cells, resulting in the inhibition of Th2 cell proliferation. The deletion of the Gfi1 gene in Th2 cells results in the failure of their proliferation, accompanied by an impaired cell cycle progression. In contrast, the enforced expression of GFI1 restores the defective Th2 cell proliferation, even in the presence of IFNγ. These results demonstrate that GFI1 is a key molecule in the IFNγ-mediated inhibition of Th2 cell proliferation.
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Affiliation(s)
- Murshed H. Sarkar
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Ryoji Yagi
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- * E-mail: (RY); (MYK)
| | - Yukihiro Endo
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- Department of Experimental Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Ryo Koyama-Nasu
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- Department of Experimental Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Yangsong Wang
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- Department of Experimental Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Ichita Hasegawa
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- Department of Experimental Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Toshihiro Ito
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Ilkka S. Junttila
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Jinfang Zhu
- Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Motoko Y. Kimura
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- Department of Experimental Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
- * E-mail: (RY); (MYK)
| | - Toshinori Nakayama
- Department of Immunology, Chiba University, Inohana, Chuo-ku, Chiba, Japan
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Transcriptome analysis revealed that delaying first colostrum feeding postponed ileum immune system development of neonatal calves. Genomics 2021; 113:4116-4125. [PMID: 34743958 DOI: 10.1016/j.ygeno.2021.10.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 10/04/2021] [Accepted: 10/14/2021] [Indexed: 11/21/2022]
Abstract
Our objective was to evaluate the effect of colostrum feeding times on genome-wide gene expression of neonatal calves. In total, twenty-seven calves were assigned to three colostrum feeding treatments: within 45 min (TRT0h, n = 9), 6 h (TRT6h, n = 9) and 12 h (TRT12h, n = 9). Ileum tissues were collected at 51 h and transcriptomic analysis was conducted. Uniquely expressed genes were identified in TRT0h group with enriched "Antigen Presentation" function. Meanwhile, the weighted gene co-expression network analysis (WGCNA) identified four significant gene modules (|correlation| > 0.50 and P ≤ 0.05). In particular, Turquoise gene module with the enriched "Cadherin binding involved in cell-cell adhesion" and "Cell-cell adherences junction" GO terms were significantly correlated with Faecalibacterium prausnitzii (R = -0.70, P < 0.01) and Bifidobacterium (R = -0.55, P < 0.01). Our findings suggest feeding colostrum without delay could stimulate the expression of genes involved in immune function development related to host response and microbial colonization in neonatal claves.
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Functional NK Cell Activation by Ovalbumin Immunization with a Monophosphoryl Lipid A and Poly I:C Combination Adjuvant Promoted Dendritic Cell Maturation. Vaccines (Basel) 2021; 9:vaccines9101061. [PMID: 34696169 PMCID: PMC8540815 DOI: 10.3390/vaccines9101061] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/19/2021] [Accepted: 09/19/2021] [Indexed: 12/02/2022] Open
Abstract
Natural killer (NK) cells are one of the types of innate immune cells to remove pathogen-infected cells and modulate inflammatory immune responses. Recent studies have revealed that NK cells could enhance vaccine efficacy by coordinating the innate and adaptive immune responses. In this study, we have evaluated the efficacy of intranasal ovalbumin (OVA) immunization with a monophosphoryl lipid A (MPL) and polyriboinosinic polyribocytidylic acid (poly I:C) combination adjuvant in promoting NK cell recruitment, differentiation, and activation. The frequencies of NK cells were positively correlated with those of dendritic cells (DCs) at the site of immunization. Moreover, the activated NK cells and DCs by the MPL + poly I:C combination adjuvant induced activations of each other cells in vitro. Taken together, this study suggested that the MPL and poly I:C combination adjuvant in OVA vaccination mediated NK cell activation and cellular crosstalk between NK cells and DCs, suggesting a promising vaccine adjuvant candidate for promoting cellular immune responses.
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Yan Z, Wang H, Mu L, Hu ZD, Zheng WQ. Regulatory roles of extracellular vesicles in immune responses against Mycobacterium tuberculosis infection. World J Clin Cases 2021; 9:7311-7318. [PMID: 34616797 PMCID: PMC8464473 DOI: 10.12998/wjcc.v9.i25.7311] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/19/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs) are cystic vesicles naturally released by most mammalian cells and bacteria. EV contents include proteins, lipids, and nucleic acids. EVs can act as messengers to transmit a variety of molecules to recipient cells and thus play important regulatory roles in intercellular signal transduction. EVs, released by either a host cell or a pathogen, can carry pathogen-associated antigens and thus act as modulators of immune responses. EVs derived from Mycobacterium tuberculosis (Mtb)-infected cells can regulate the innate immune response through various pathways, such as regulating the release of inflammatory cytokines. In addition, EVs can mediate antigen presentation and regulate the adaptive immune response by transmitting immunoregulatory molecules to T helper cells. In this review, we summarize the regulatory roles of EVs in the immune response against Mtb.
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Affiliation(s)
- Zhi Yan
- Department of Laboratory Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
- Department of Parasitology, the College of Basic Medical Sciences of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Hua Wang
- Department of Laboratory Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
- Department of Parasitology, the College of Basic Medical Sciences of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Lan Mu
- Department of Parasitology, the College of Basic Medical Sciences of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Zhi-De Hu
- Department of Laboratory Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
| | - Wen-Qi Zheng
- Department of Laboratory Medicine, the Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
- Department of Parasitology, the College of Basic Medical Sciences of Inner Mongolia Medical University, Hohhot 010050, Inner Mongolia Autonomous Region, China
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Ding L, Dong HY, Zhou TR, Wang YH, Yan T, Li JC, Wang ZY, Li J, Liang C. PD-1/PD-L1 inhibitors-based treatment for advanced renal cell carcinoma: Mechanisms affecting efficacy and combination therapies. Cancer Med 2021; 10:6384-6401. [PMID: 34382349 PMCID: PMC8446416 DOI: 10.1002/cam4.4190] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 12/14/2022] Open
Abstract
With the widespread use of PD-1/PD-L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD-1/PD-L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD-L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD-1/PD-L1 mAb in the treatment of aRCC, and CTLA-4 mAb has been shown to have a non-redundant effect with PD-1/PD-L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD-1/PD-L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/metabolism
- Carcinoma, Renal Cell/diagnosis
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/immunology
- Carcinoma, Renal Cell/mortality
- Cell Line, Tumor
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/immunology
- Drug Screening Assays, Antitumor
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Immune Checkpoint Inhibitors/pharmacology
- Immune Checkpoint Inhibitors/therapeutic use
- Kidney Neoplasms/diagnosis
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/immunology
- Kidney Neoplasms/mortality
- Mutation
- Programmed Cell Death 1 Receptor/antagonists & inhibitors
- Programmed Cell Death 1 Receptor/metabolism
- Progression-Free Survival
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
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Affiliation(s)
- Lei Ding
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Hui yu Dong
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Tian ren Zhou
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Yu hao Wang
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Tao Yan
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jun chen Li
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Zhong yuan Wang
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jie Li
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Chao Liang
- Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
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Differential responses of chicken monocyte-derived dendritic cells infected with Salmonella Gallinarum and Salmonella Typhimurium. Sci Rep 2021; 11:17214. [PMID: 34446765 PMCID: PMC8390485 DOI: 10.1038/s41598-021-96527-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/11/2021] [Indexed: 11/08/2022] Open
Abstract
Salmonella enterica serovar Gallinarum is a host-restricted bacterial pathogen that causes a serious systemic disease exclusively in birds of all ages. Salmonella enterica serovar Typhimurium is a host-generalist serovar. Dendritic cells (DCs) are key antigen-presenting cells that play an important part in Salmonella host-restriction. We evaluated the differential response of chicken blood monocyte-derived dendritic cells (chMoDCs) exposed to S. Gallinarum or S. Typhimurium. S. Typhimurium was found to be more invasive while S. Gallinarum was more cytotoxic at the early phase of infection and later showed higher resistance against chMoDCs killing. S. Typhimurium promoted relatively higher upregulation of costimulatory and other immune function genes on chMoDCs in comparison to S. Gallinarum during early phase of infection (6 h) as analyzed by real-time PCR. Both Salmonella serovars strongly upregulated the proinflammatory transcripts, however, quantum was relatively narrower with S. Gallinarum. S. Typhimurium-infected chMoDCs promoted relatively higher proliferation of naïve T-cells in comparison to S. Gallinarum as assessed by mixed lymphocyte reaction. Our findings indicated that host restriction of S. Gallinarum to chicken is linked with its profound ability to interfere the DCs function. Present findings provide a valuable roadmap for future work aimed at improved vaccine strategies against this pathogen.
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CpG-ODN Signaling via Dendritic Cells-Expressing MyD88, but Not IL-10, Inhibits Allergic Sensitization. Vaccines (Basel) 2021; 9:vaccines9070743. [PMID: 34358159 PMCID: PMC8310155 DOI: 10.3390/vaccines9070743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 11/17/2022] Open
Abstract
Allergen-specific T helper (Th)2 cells orchestrate upon allergen challenge the development of allergic eosinophilic lung inflammation. Sensitization with alum adjuvant, a type 2 adjuvant, has been used extensively in animal models of allergic lung disease. In contrast, type 1 adjuvants like CpG-ODN, a synthetic toll-like receptor 9 agonist, inhibit the development of Th2 immunity. CpG-ODN induce type 1 and suppressive cytokines that influence Th2 cell differentiation. Here, we investigated the immune modulatory effect of CpG-ODN on allergic sensitization to OVA with alum focusing on dendritic cells (DCs) expressing the MyD88 molecule and the suppressive IL-10 cytokine. Using mice with specific cell deletion of MyD88 molecule, we showed that CpG-ODN suppressed allergic sensitization and consequent lung allergic inflammation signaling through the MyD88 pathway on dendritic cells, but not on B-cells. This inhibition was associated with an increased production of IL-10 in the bronchoalveolar lavage fluid. Sensitization to OVA with CpG-ODN of IL-10-deficient, but not wild-type mice, induced a shift towards Th1 pattern of inflammation. Employing bone marrow-derived dendritic cells (BM-DCs) pulsed with OVA for sensitizations with or without CpG-ODN, we showed that IL-10 is dispensable for the inhibition of allergic lung Th2 responses by CpG-ODN. Moreover, the lack of IL-10 on DCs was not sufficient for the CpG-ODN-induced immune-deviation towards a Th1 pattern. Accordingly, we confirmed directly the role of MyD88 pathway on DCs in the inhibition of allergic sensitization.
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Hu Y, Zhao Z, Ehrich M, Zhang C. Formulation of Nanovaccines toward an Extended Immunity against Nicotine. ACS APPLIED MATERIALS & INTERFACES 2021; 13:27972-27982. [PMID: 34105952 PMCID: PMC9201939 DOI: 10.1021/acsami.1c07049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Nicotine vaccines have been investigated to assist with smoking cessation. Because smoking cessation is a long process, past nicotine vaccines required multiple injections to achieve long-term efficacy. It would be of great significance if extended efficacy can be achieved with fewer injections. Here, we report the assembly of lipid-polylactic acid (PLA) and lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) based nicotine vaccines. Mice immunized with the lipid-PLGA vaccine produced higher titers of nicotine-specific antibodies than the lipid-PLA vaccine in short-term. However, the lipid-PLA vaccine was found to induce long-lasting antibodies. Three months after the immunization, only mice that received first two injections of the lipid-PLGA vaccine and a third injection of the lipid-PLA vaccine achieved a significantly lower brain nicotine concentration of 65.13 ± 20.59 ng/mg than 115.88 ± 37.62 ng/mg from the negative controls. The results indicate that not only the stability of the vaccines but also the combination of the vaccines impacted the long-term efficacy of the immunization. Lastly, both the body weight and the histopathology study suggest that the vaccines were safe to mice. These findings suggest that long-term immunity against nicotine can be realized by a rational administration of nanovaccines of different levels of stability.
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Affiliation(s)
- Yun Hu
- Department of Biological Systems Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Zongmin Zhao
- Department of Biological Systems Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Marion Ehrich
- Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia 24061, United States
| | - Chenming Zhang
- Department of Biological Systems Engineering, Virginia Tech, Blacksburg, Virginia 24061, United States
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Poholek AC. Tissue-Specific Contributions to Control of T Cell Immunity. Immunohorizons 2021; 5:410-423. [PMID: 34103371 PMCID: PMC10876086 DOI: 10.4049/immunohorizons.2000103] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/17/2021] [Indexed: 11/19/2022] Open
Abstract
T cells are critical for orchestrating appropriate adaptive immune responses and maintaining homeostasis in the face of persistent nonpathogenic Ags. T cell function is controlled in part by environmental signals received upon activation and derived from the tissue environment in which Ag is encountered. Indeed, tissue-specific environments play important roles in controlling the T cell response to Ag, and recent evidence suggests that tissue draining lymph nodes can mirror those local differences. Thus, tissue-specific immunity may begin at priming in secondary lymph nodes, where local signals have an important role in T cell fate. In this study, we discuss the tissue-specific signals that may impact T cell differentiation and function, including the microbiome, metabolism, and tissue-specific innate cell imprinting. We argue that these individual contributions create tissue-specific niches that likely play important roles in T cell differentiation and function controlling the outcome of the response to Ags.
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Affiliation(s)
- Amanda C Poholek
- Division of Pediatric Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA; and Department of Immunology, University of Pittsburgh, Pittsburgh, PA
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44
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Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses. Blood Adv 2021; 4:3572-3585. [PMID: 32761232 DOI: 10.1182/bloodadvances.2019001410] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/01/2020] [Indexed: 11/20/2022] Open
Abstract
Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.
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45
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Impact of Immunotherapy on CD4 T Cell Phenotypes and Function in Cancer. Vaccines (Basel) 2021; 9:vaccines9050454. [PMID: 34064410 PMCID: PMC8147771 DOI: 10.3390/vaccines9050454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 04/29/2021] [Accepted: 05/02/2021] [Indexed: 12/29/2022] Open
Abstract
Immunotherapy has become a standard treatment in many cancers and it is based on three main therapeutic axes: immune checkpoint blockade (ICB), vaccination and adoptive cell transfer (ACT). If originally these therapies mainly focused on exploiting CD8 T cells given their role in the direct elimination of tumor cells, increasing evidence highlights the crucial role CD4 T cells play in the antitumor immune response. Indeed, these cells can profoundly modulate the tumor microenvironment (TME) by secreting different types of cytokine or by directly eliminating cancer cells. In this review, we describe how different CD4 T cell subsets can contribute to tumor immune responses during immunotherapy and the novel high-throughput immune monitoring tools that are expected to facilitate the study of CD4 T cells, at antigen-specific and single cell level, thus accelerating bench-to-bed translational research in cancer.
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Leite Dantas R, Freff J, Ambrée O, Beins EC, Forstner AJ, Dannlowski U, Baune BT, Scheu S, Alferink J. Dendritic Cells: Neglected Modulators of Peripheral Immune Responses and Neuroinflammation in Mood Disorders? Cells 2021; 10:941. [PMID: 33921690 PMCID: PMC8072712 DOI: 10.3390/cells10040941] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 03/25/2021] [Accepted: 04/07/2021] [Indexed: 12/11/2022] Open
Abstract
Affective disorders (AD) including major depressive disorder (MDD) and bipolar disorder (BD) are common mood disorders associated with increased disability and poor health outcomes. Altered immune responses characterized by increased serum levels of pro-inflammatory cytokines and neuroinflammation are common findings in patients with AD and in corresponding animal models. Dendritic cells (DCs) represent a heterogeneous population of myeloid cells that orchestrate innate and adaptive immune responses and self-tolerance. Upon sensing exogenous and endogenous danger signals, mature DCs secrete proinflammatory factors, acquire migratory and antigen presenting capacities and thus contribute to neuroinflammation in trauma, autoimmunity, and neurodegenerative diseases. However, little is known about the involvement of DCs in the pathogenesis of AD. In this review, we summarize the current knowledge on DCs in peripheral immune responses and neuroinflammation in MDD and BD. In addition, we consider the impact of DCs on neuroinflammation and behavior in animal models of AD. Finally, we will discuss therapeutic perspectives targeting DCs and their effector molecules in mood disorders.
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Affiliation(s)
- Rafael Leite Dantas
- Department of Mental Health, University of Münster, 48149 Münster, Germany; (R.L.D.); (J.F.); (U.D.); (B.T.B.)
- Cells in Motion Interfaculty Centre, University of Münster, 48149 Münster, Germany
| | - Jana Freff
- Department of Mental Health, University of Münster, 48149 Münster, Germany; (R.L.D.); (J.F.); (U.D.); (B.T.B.)
- Cells in Motion Interfaculty Centre, University of Münster, 48149 Münster, Germany
| | - Oliver Ambrée
- Department of Behavioural Biology, University of Osnabrück, 49076 Osnabrück, Germany;
- Center of Cellular Nanoanalytics, University of Osnabrück, 49076 Osnabrück, Germany
| | - Eva C. Beins
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, 53127 Bonn, Germany; (E.C.B.); (A.J.F.)
| | - Andreas J. Forstner
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, 53127 Bonn, Germany; (E.C.B.); (A.J.F.)
- Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, 52428 Jülich, Germany
| | - Udo Dannlowski
- Department of Mental Health, University of Münster, 48149 Münster, Germany; (R.L.D.); (J.F.); (U.D.); (B.T.B.)
| | - Bernhard T. Baune
- Department of Mental Health, University of Münster, 48149 Münster, Germany; (R.L.D.); (J.F.); (U.D.); (B.T.B.)
- Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Parkville, VIC 3010, Australia
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Stefanie Scheu
- Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, 40225 Düsseldorf, Germany;
| | - Judith Alferink
- Department of Mental Health, University of Münster, 48149 Münster, Germany; (R.L.D.); (J.F.); (U.D.); (B.T.B.)
- Cells in Motion Interfaculty Centre, University of Münster, 48149 Münster, Germany
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Yao L, Hu Q, Chen S, Zhou T, Yu X, Ma H, H. Ghonaim A, Wu H, Sun Q, Fan S, He Q. Recombinant Pseudorabies Virus with TK/gE Gene Deletion and Flt3L Co-Expression Enhances the Innate and Adaptive Immune Response via Activating Dendritic Cells. Viruses 2021; 13:v13040691. [PMID: 33923590 PMCID: PMC8072707 DOI: 10.3390/v13040691] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/08/2021] [Accepted: 04/09/2021] [Indexed: 12/23/2022] Open
Abstract
Owing to viral evolution and recombination, emerging pseudorabies virus (PRV) strains have caused unprecedented outbreaks in swine farms even when the pigs were previously vaccinated, which might indicate that traditional vaccines were unable to provide effective protection. The development of safe and efficacious vaccines presents prospects to minimize the clinical signs and eventually eradicate the infection. In this study, we used an emerging PRV strain, HNX, as the parental strain to construct a recombinant PRV with TK/gE gene deletion and Fms-related tyrosine kinase 3 ligand (Flt3L) expression, named HNX-TK−/gE−-Flt3L. HNX-TK−/gE−-Flt3L enhanced the maturation of bone marrow derived dendritic cells (DCs) in vitro. Significantly more activated DCs were detected in HNX-TK−/gE−-Flt3L-immunized mice compared with those immunized with HNX-TK−/gE−. Subsequently, a remarkable increase of neutralizing antibodies, gB-specific IgG antibodies, and interferon-gamma (IFN-γ) was observed in mice vaccinated with HNX-TK−/gE−-Flt3L. In addition, a lower mortality and less histopathological damage were observed in HNX-TK−/gE−-Flt3L vaccinated mice with upon PRV lethal challenge infection. Taken together, our results revealed the potential of Flt3L as an ideal adjuvant that can activate DCs and enhance protective immune responses and support the further evaluation of HNX-TK−/gE−-Flt3L as a promising PRV vaccine candidate.
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Affiliation(s)
- Lun Yao
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Qiao Hu
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Siqi Chen
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
| | - Tong Zhou
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
| | - Xuexiang Yu
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Hailong Ma
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Ahmed. H. Ghonaim
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
- Desert Research Center, Cairo 11435, Egypt
| | - Hao Wu
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Qi Sun
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Shengxian Fan
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
| | - Qigai He
- State Key Laboratory of Agricultural Microbiology College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China; (L.Y.); (Q.H.); (S.C.); (T.Z.); (X.Y.); (H.M.); (A.H.G.); (H.W.); (Q.S.); (S.F.)
- The Cooperative Innovation Center for Sustainable Pig Production, Huazhong Agricultural University, Wuhan 430000, China
- Correspondence: ; Tel.: +86-27-8728-6974; Fax: +86-27-8728-7288
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48
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Mota CA, Oyama J, Souza Terron Monich MD, Brustolin AÁ, Perez de Souza JV, Murase LS, Ghiraldi Lopes LD, Silva Santos TD, Vieira Teixeira JJ, Verzignassi Silveira TG. Three decades of clinical trials on immunotherapy for human leishmaniases: a systematic review and meta-analysis. Immunotherapy 2021; 13:693-721. [PMID: 33853344 DOI: 10.2217/imt-2020-0184] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Aim: Current treatments for leishmaniases are not satisfactory, thus alternatives are needed. We searched for clinical trials with immunotherapeutic approaches for patients with leishmaniasis. Materials & methods: Out of 205 articles, 24 clinical trials were selected, and eight submitted to meta-analysis. Results: A reduction in healing time was observed in patients with tegumentary leishmaniasis treated with pentavalent antimony plus granulocyte-macrophage colony-stimulating factor, and therapeutic vaccines. Overall meta-analysis indicated that immunotherapy associated with the standard chemotherapy generated a significantly reduced risk of treatment failure than the pentavalent antimony alone (p = 0.03). Conclusion: Our review confirmed the efficacy of immunotherapies for the treatment of cutaneous and visceral leishmaniasis and highlighted the importance of clinical trials using immunotherapies for leishmaniases.
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Affiliation(s)
- Camila Alves Mota
- Graduate Program in Health Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | - Jully Oyama
- Graduate Program in Bioscience & Physiopathology, State University of Maringá, Maringá, Paraná, Brazil
| | | | - Aline Ávila Brustolin
- Graduate Program in Health Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | - João Vítor Perez de Souza
- Graduate Program in Bioscience & Physiopathology, State University of Maringá, Maringá, Paraná, Brazil
| | - Letícia Sayuri Murase
- Graduate Program in Health Sciences, State University of Maringá, Maringá, Paraná, Brazil
| | - Luciana Dias Ghiraldi Lopes
- Laboratory of Clinical Virology, Department of Clinical Analysis & Biomedicine, State University of Maringá, Maringá, Paraná, Brazil
| | - Thais da Silva Santos
- Graduate Program in Bioscience & Physiopathology, State University of Maringá, Maringá, Paraná, Brazil
| | - Jorge Juarez Vieira Teixeira
- Laboratory of Leishmaniases, Department of Clinical Analysis & Biomedicine, State University of Maringá, Maringá, Paraná, Brazil
| | - Thaís Gomes Verzignassi Silveira
- Laboratory of Leishmaniases, Department of Clinical Analysis & Biomedicine, State University of Maringá, Maringá, Paraná, Brazil
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Immunotherapy in treatment of leishmaniasis. Immunol Lett 2021; 233:80-86. [PMID: 33771555 DOI: 10.1016/j.imlet.2021.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/12/2021] [Accepted: 03/19/2021] [Indexed: 11/21/2022]
Abstract
Leishmaniasis caused by various species of protozoan transmitted by sand fly vectors occurs as a spectrum of clinical features including cutaneous, mucocutaneous and visceral forms. It is a geographically distributed parasitic disease and a major public health problem in the world. The clinical syndromes are highly variable depending on the parasite species, host genetics, vectors and environment. To date, there is no effective vaccine and traditional treatments are toxic, expensive with long administration duration and many adverse side effects and/or drug resistance. Instead of treatments based on chemotherapy, certain strategies aim to recover leishmaniasis and reduce the parasitic burden. Immunotherapy has focused on the induction of effective immune response to rapidly control the disease. Recent studies have indicated that a single dose of a suitable therapeutic vaccine induces a quick and lasting recovery in patients. Immunotherapy reduces the toxicity of drug and the emergence of resistance dramatically. It could be an effective addition to chemotherapy with a safe and potent drug compared with monotherapy, resulting in a prophylactic and therapeutic cure of leishmaniasis. This review has focused on treatment of leishmaniasis with particular emphasis on immunotherapy as an alternative to conventional drug treatment.
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50
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Pathogen Dose in Animal Models of Hemorrhagic Fever Virus Infections and the Potential Impact on Studies of the Immune Response. Pathogens 2021; 10:pathogens10030275. [PMID: 33804381 PMCID: PMC7999429 DOI: 10.3390/pathogens10030275] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 12/24/2022] Open
Abstract
Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and have been crucial for the development of therapeutics and vaccines that have been approved for human use. Most of these models use artificially high doses of virus, ensuring lethality in pre-clinical drug development studies. However, this can have a significant effect on the immune response generated. Here I discuss how the dose of antigen or pathogen is a critical determinant of immune responses and suggest that the current study of viruses in animal models should take this into account when developing and studying animal models of disease. This can have implications for determination of immune correlates of protection against disease as well as informing relevant vaccination and therapeutic strategies.
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