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1
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Martin J, Hollowood Z, Chorlton J, Dyer C, Marelli-Berg F. Modulating regulatory T cell migration in the treatment of autoimmunity and autoinflammation. Curr Opin Pharmacol 2024; 77:102466. [PMID: 38906084 DOI: 10.1016/j.coph.2024.102466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/23/2024]
Abstract
Treatment of autoimmunity and autoinflammation with regulatory T cells has received much attention in the last twenty years. Despite the well-documented clinical benefit of Treg therapy, a large-scale application has proven elusive, mainly due to the extensive culture facilities required and associated costs. A possible way to overcome these hurdles in part is to target Treg migration to inflammatory sites using a small molecule. Here we review recent advances in this strategy and introduce the new concept of pharmacologically enhanced delivery of endogenous Tregs to control inflammation, which has been recently validated in humans.
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Affiliation(s)
- John Martin
- Division of Medicine, University College London, London, WC1E 6JF, UK; St George Street Capital, London, EC4R 1BE, UK.
| | | | | | - Carlene Dyer
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Federica Marelli-Berg
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
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2
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Khan MA, Lau CL, Krupnick AS. Monitoring regulatory T cells as a prognostic marker in lung transplantation. Front Immunol 2023; 14:1235889. [PMID: 37818354 PMCID: PMC10561299 DOI: 10.3389/fimmu.2023.1235889] [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: 06/06/2023] [Accepted: 09/11/2023] [Indexed: 10/12/2023] Open
Abstract
Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates.
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3
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Olesiejuk K, Chałubiński M. How does particulate air pollution affect barrier functions and inflammatory activity of lung vascular endothelium? Allergy 2023; 78:629-638. [PMID: 36588285 DOI: 10.1111/all.15630] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/17/2022] [Accepted: 12/20/2022] [Indexed: 01/03/2023]
Abstract
Both particulate matter and gaseous components of air pollution have already been shown to increase cardiovascular mortality in numerous studies. It is, however, important to note that on their way to the bloodstream the polluting agents pass the lung barrier. Inside the alveoli, particles of approximately 0.4-1 μm are most efficiently deposited and commonly undergo phagocytosis by lung macrophages. Not only the soluble agents, but also particles fine enough to leave the alveoli enter the bloodstream in this finite part of the endothelium, reaching thus higher concentrations in close proximity of the alveoli and endothelium. Additionally, deposits of particulate matter linger in direct proximity of the endothelial cells and may induce inflammation, immune responses, and influence endothelial barrier dysfunction thus increasing PM bioavailability in positive feedback. The presented discussion provides an overview of possible components of indoor PM and how endothelium is thus influenced, with emphasis on lung vascular endothelium and clinical perspectives.
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Affiliation(s)
- Krzysztof Olesiejuk
- Department of Immunology and Allergy, Chair of Pulmonology, Rheumatology and Clinical Immunology, Medical University of Lodz, Lodz, Poland
| | - Maciej Chałubiński
- Department of Immunology and Allergy, Chair of Pulmonology, Rheumatology and Clinical Immunology, Medical University of Lodz, Lodz, Poland
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4
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Li HS, Wong NM, Tague E, Ngo JT, Khalil AS, Wong WW. High-performance multiplex drug-gated CAR circuits. Cancer Cell 2022; 40:1294-1305.e4. [PMID: 36084652 PMCID: PMC9669166 DOI: 10.1016/j.ccell.2022.08.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 01/09/2023]
Abstract
Chimeric antigen receptor (CAR) T cells can revolutionize cancer medicine. However, overactivation, lack of tumor-specific surface markers, and antigen escape have hampered CAR T cell development. A multi-antigen targeting CAR system regulated by clinically approved pharmaceutical agents is needed. Here, we present VIPER CARs (versatile protease regulatable CARs), a collection of inducible ON and OFF switch CAR circuits engineered with a viral protease domain. We established their controllability using FDA-approved antiviral protease inhibitors in a xenograft tumor and a cytokine release syndrome mouse model. Furthermore, we benchmarked VIPER CARs against other drug-gated systems and demonstrated best-in-class performance. We showed their orthogonality in vivo using the ON VIPER CAR and OFF lenalidomide-CAR systems. Finally, we engineered several VIPER CAR circuits by combining various CAR technologies. Our multiplexed, drug-gated CAR circuits represent the next progression in CAR design capable of advanced logic and regulation for enhancing the safety of CAR T cell therapy.
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Affiliation(s)
- Hui-Shan Li
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - Nicole M Wong
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - Elliot Tague
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - John T Ngo
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA
| | - Ahmad S Khalil
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Wilson W Wong
- Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.
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5
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Harada Y, Miyamoto K, Chida A, Okuzawa AT, Yoshimatsu Y, Kudo Y, Sujino T. Localization and movement of Tregs in gastrointestinal tract: a systematic review. Inflamm Regen 2022; 42:47. [PMID: 36329556 PMCID: PMC9632047 DOI: 10.1186/s41232-022-00232-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The intestine is rich in food-derived and microbe-derived antigens. Regulatory T cells (Tregs) are an essential T-cell population that prevents systemic autoimmune diseases and inhibits inflammation by encountering antigens. Previously, it was reported that the functional loss of Tregs induces systemic inflammation, including inflammatory bowel disease and graft-versus-host disease in human and murine models. However, there is a dearth of information about how Tregs localize in different tissues and suppress effector cells. MAIN BODY The development of Tregs and their molecular mechanism in the digestive tract have been elucidated earlier using murine genetic models, infectious models, and human samples. Tregs suppress immune and other nonimmune cells through direct effect and cytokine production. The recent development of in vivo imaging technology allows us to visualize how Tregs localize and move in the settings of inflammation and homeostasis. This is important because, according to a recent report, Treg characterization and function are regulated by their location. Tregs located in the proximal intestine and its draining lymph nodes induce tolerance against food antigens, and those located in the distal intestine suppress the inflammation induced by microbial antigens. Taken together, various Tregs are induced in a location-specific manner in the gastrointestinal tract and influence the homeostasis of the gut. CONCLUSION In this review, we summarize how Tregs are induced in the digestive tract and the application of in vivo Treg imaging to elucidate immune homeostasis in the digestive tract.
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Affiliation(s)
- Yosuke Harada
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Kentaro Miyamoto
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan.,Miyarisan Pharm. Co. Ltd, Tokyo, Japan
| | - Akihiko Chida
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Anna Tojo Okuzawa
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Yusuke Yoshimatsu
- Department of Gastroenterology and Hepatology, School of Medicine, Keio University, Tokyo, Japan
| | - Yumi Kudo
- Department of Pediatric Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Tomohisa Sujino
- Center for the Diagnostic and Therapeutic Endoscopy, School of Medicine, Keio University, Tokyo, Japan.
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6
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Muacevic A, Adler JR. Classic and Current Opinions in Human Organ and Tissue Transplantation. Cureus 2022; 14:e30982. [PMID: 36337306 PMCID: PMC9624478 DOI: 10.7759/cureus.30982] [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] [Accepted: 11/01/2022] [Indexed: 11/30/2022] Open
Abstract
Graft tolerance is a pathophysiological condition heavily reliant on the dynamic interaction of the innate and adaptive immune systems. Genetic polymorphism determines immune responses to tissue/organ transplantation, and intricate humoral and cell-mediated mechanisms control these responses. In transplantation, the clinician's goal is to achieve a delicate equilibrium between the allogeneic immune response, undesired effects of the immunosuppressive drugs, and the existing morbidities that are potentially life-threatening. Transplant immunopathology involves sensitization, effector, and apoptosis phases which recruit and engages immunological cells like natural killer cells, lymphocytes, neutrophils, and monocytes. Similarly, these cells are involved in the transfer of normal or genetically engineered T cells. Advances in tissue transplantation would involve a profound knowledge of the molecular mechanisms that underpin the respective immunopathology involved and the design of precision medicines that are safe and effective.
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7
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Yeo WS, Ng QX. Biomarkers of immune tolerance in kidney transplantation: an overview. Pediatr Nephrol 2022; 37:489-498. [PMID: 33712863 DOI: 10.1007/s00467-021-05023-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 02/09/2021] [Accepted: 02/19/2021] [Indexed: 11/30/2022]
Abstract
Kidney failure, one of the most prevalent diseases in the world and with increasing incidence, is associated with substantial morbidity and mortality. Currently available modes of kidney replacement therapy include dialysis and kidney transplantation. Though kidney transplantation is the preferred and ideal mode of kidney replacement therapy, this modality, however, is not without its risks. Kidney transplant recipients are constantly at risk of complications associated with immunosuppression, namely, opportunistic infections (e.g., Epstein-Barr virus and cytomegalovirus infections), post-transplant lymphoproliferative disorder, and complications associated with immunosuppressants (e.g., calcineurin inhibitor- and corticosteroid-associated new onset diabetes after transplantation and calcineurin inhibitor-associated nephrotoxicity). Transplantation tolerance, an acquired state in which immunocompetent recipients have developed donor-specific unresponsiveness, may be the Holy Grail in enabling optimal allograft survival and obviating the risks associated with immunosuppression in kidney transplant recipients. This review aims to discuss the biomarkers available to predict, identify, and define the transplant immune tolerant state and various tolerance induction strategies. Regrettably, pediatric patients have not been included in any tolerance studies and this should be the focus of future studies.
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Affiliation(s)
- Wee-Song Yeo
- Mount Elizabeth Hospital, 3 Mount Elizabeth, Singapore, 228510, Singapore.
| | - Qin Xiang Ng
- MOH Holdings Pte Ltd, 1 Maritime Square, Singapore, 099253, Singapore
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8
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Repression of T cell-mediated alloimmunity by CX-5461 via the p53-DUSP5 pathway. Pharmacol Res 2022; 177:106120. [DOI: 10.1016/j.phrs.2022.106120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/30/2022] [Accepted: 02/03/2022] [Indexed: 12/19/2022]
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9
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Anggelia MR, Cheng HY, Lai PC, Hsieh YH, Lin CH, Lin CH. Cell Therapy in Vascularized Composite Allotransplantation. Biomed J 2022; 45:454-464. [PMID: 35042019 PMCID: PMC9422067 DOI: 10.1016/j.bj.2022.01.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 12/02/2021] [Accepted: 01/10/2022] [Indexed: 11/18/2022] Open
Abstract
Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation (VCA). Treatments of graft rejection with lifelong immunosuppression (IS) subject the recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.
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Affiliation(s)
- Madonna Rica Anggelia
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ping-Chin Lai
- The Kidney Institute and Division of Nephrology, China Medical University Hospital, Taichung, Taiwan
| | - Yun-Huan Hsieh
- Department of Plastic and Reconstructive Surgery, Epworth Eastern Hospital, Victoria, Australia
| | - Chih-Hung Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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10
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Rickert CG, Markmann JF. Transplantation in the Age of Precision Medicine: The Emerging Field of Treg Therapy. Semin Nephrol 2022; 42:76-85. [DOI: 10.1016/j.semnephrol.2022.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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11
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Hall BM, Hall RM, Tran GT, Robinson CM, Wilcox PL, Rakesh PK, Wang C, Sharland AF, Verma ND, Hodgkinson SJ. Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4 +CD25 + Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor. Front Immunol 2021; 12:714838. [PMID: 34912327 PMCID: PMC8667344 DOI: 10.3389/fimmu.2021.714838] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 11/01/2021] [Indexed: 12/26/2022] Open
Abstract
CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells' activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts' CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.
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Affiliation(s)
- Bruce M Hall
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Rachael M Hall
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Giang T Tran
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Catherine M Robinson
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Paul L Wilcox
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Prateek K Rakesh
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Chuanmin Wang
- Transplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Alexandra F Sharland
- Transplantation Immunobiology Group, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Nirupama D Verma
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
| | - Suzanne J Hodgkinson
- Immune Tolerance Laboratory, South West Clinical School, University of New South Wales (UNSW) Sydney, Liverpool, NSW, Australia.,Ingham Institute of Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia
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12
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Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
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Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
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13
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Mansourabadi AH, Mohamed Khosroshahi L, Noorbakhsh F, Amirzargar A. Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with the focus on Tregs, CAR Tregs, and Mesenchymal stem cells. Int Immunopharmacol 2021; 97:107669. [PMID: 33965760 DOI: 10.1016/j.intimp.2021.107669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Organ transplantation is a practical treatment for patients with end-stage organ failure. Despite the advances in short-term graft survival, long-term graft survival remains the main challenge considering the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressive drugs. Since a novel therapeutic strategy to induce allograft tolerance seems urgent, focusing on developing novel and safe approaches to prolong graft survival is one of the main goals of transplant investigators. Researchers in the field of organ transplantation are interested in suppressing or optimizing the immune responses by focusing on immune cells including mesenchymal stem cells (MSCs), polyclonal regulatory Tcells (Tregs), and antigen-specific Tregs engineered with chimeric antigen receptors (CAR Tregs). We review the mechanistic pathways, phenotypic and functional characteristics of these cells, and their promising application in organ transplantation.
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Affiliation(s)
- Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran; Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran
| | - Leila Mohamed Khosroshahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
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14
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Aghabi YO, Yasin A, Kennedy JI, Davies SP, Butler AE, Stamataki Z. Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer. Front Immunol 2021; 12:662134. [PMID: 33953725 PMCID: PMC8089374 DOI: 10.3389/fimmu.2021.662134] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
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Affiliation(s)
| | | | | | | | | | - Zania Stamataki
- College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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15
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Keller CC, Eikmans M, van der Hoorn MLP, Lashley LEELO. Recurrent miscarriages and the association with regulatory T cells; A systematic review. J Reprod Immunol 2020; 139:103105. [PMID: 32199194 DOI: 10.1016/j.jri.2020.103105] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 02/01/2020] [Accepted: 03/03/2020] [Indexed: 01/05/2023]
Abstract
Regulatory T cells (Tregs) are essential in tolerizing the maternal immune system toward the semi-allogeneic embryo. In this systematic review, we evaluated the association of levels and function of Tregs in peripheral blood and decidua with recurrent miscarriage (RM), defined as two unexplained miscarriages. We included 18 studies. Ten studies showed a significantly decreased level of Tregs in peripheral blood of non-pregnant women with RM, compared to controls (p < 0.05). In pregnant women with RM, levels of Tregs in the peripheral blood were significantly lower compared to control groups (p = 0.0004), as shown in nine studies. Moreover, seven studies described a decrease of Treg levels in the placenta of pregnant women with RM (p < 0.0001) compared to controls. Accordingly, the median of the relative changes (MRC) between cases and controls in the non-pregnant group (peripheral blood), and the two pregnant groups (peripheral blood and decidua) were -0.18 (-0.27-0), -0.26 (-0.35 to -0.17), and -0.52 (0.63--0.31), respectively. In addition to the assessment of Tregs by phenotype, six out of the 18 included studies investigated the functionality of these cells. These studies showed a lower inhibitory effect of Tregs cells on the proliferation of effector T cells of women with RM compared to fertile women. Also, the expression of IL-10 and TGF-beta was diminished. This systematic review shows that Treg levels and their function are significantly decreased in peripheral blood and decidua of pregnant and non-pregnant women with RM. This underlines the hypothesis that Tregs play a role in the pathogenesis of RM.
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Affiliation(s)
- Caroline C Keller
- Department of Obstetrics & Gynaecology, Erasmus Medical Center, School of Medicine, Rotterdam, the Netherlands
| | - Michael Eikmans
- Department of Immunohematology and Bloodtransfusion, Leiden University Medical Centre, Leiden, the Netherlands
| | | | - Lisa E E L O Lashley
- Department of Obstetrics and Gynecology, Leiden University Medical Center, Leiden, the Netherlands.
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16
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Tahvildari M, Dana R. Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2019; 203:2749-2755. [PMID: 31740549 PMCID: PMC6986328 DOI: 10.4049/jimmunol.1900733] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/06/2019] [Indexed: 12/24/2022]
Abstract
Regulatory T cells (Tregs) play a central role in the induction and maintenance of immune homeostasis and self-tolerance. Tregs constantly express the high-affinity receptor to IL-2. IL-2 is a pleiotropic cytokine and a key survival factor for Tregs. It maintains Tregs' suppressive function by promoting Foxp3 expression and subsequent production of immunoregulatory cytokines. Administration of low-dose IL-2 is shown to be a promising approach to prevent allograft rejection and to treat autoimmune and inflammatory conditions in experimental models. The combination of IL-2 with its mAb (JES6-1) has also been shown to increase the t 1/2 of IL-2 and further enhance Treg frequencies and function. Low-dose IL-2 therapy has been used in several clinical trials to treat conditions such as hepatitis C vasculitis, graft-versus-host disease, type 1 diabetes, and systemic lupus erythematosus. In this paper, we summarize our findings on low-dose IL-2 treatment in corneal allografting and review recent studies focusing on the use of low-dose IL-2 in transplantation, autoimmunity, and other inflammatory conditions. We also discuss potential areas of further investigation with the aim to optimize current low-dose IL-2 regimens.
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Affiliation(s)
- Maryam Tahvildari
- Kresge Eye Institute, Wayne State University, Detroit, MI 48201; and
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114
| | - Reza Dana
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114
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17
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Verma ND, Robinson CM, Carter N, Wilcox P, Tran GT, Wang C, Sharland A, Nomura M, Plain KM, Bishop GA, Hodgkinson SJ, Hall BM. Alloactivation of Naïve CD4 +CD8 -CD25 +T Regulatory Cells: Expression of CD8α Identifies Potent Suppressor Cells That Can Promote Transplant Tolerance Induction. Front Immunol 2019; 10:2397. [PMID: 31681288 PMCID: PMC6802415 DOI: 10.3389/fimmu.2019.02397] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 09/24/2019] [Indexed: 01/08/2023] Open
Abstract
Therapy with alloantigen-specific CD4+CD25+ T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4+CD25+Foxp3+Treg. After culture of naïve DA CD4+CD8−CD25+T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10–20% and CD8β on <5% of these cells. These cells expressed ifngr and Il12rb2. CD8α+ cells had increased Ifngr that characterizes Ts1 cells as well was Irf4, a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4+CD8α+CD25+Treg consistent with the CD8α+ cells expressing IL-12R. In MLC, the CD8α+ fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4+CD8−CD25+T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α+ cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4+CD8−CD25+Foxp3+T cells was a marker of activated and potent Treg that included alloantigen-specific Treg.
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Affiliation(s)
- Nirupama D Verma
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - Catherine M Robinson
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - Nicole Carter
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - Paul Wilcox
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - Giang T Tran
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - Chaunmin Wang
- Transplantation Immunobiology Research Group, Faculty of Medicine and Health, Charles Perkins Centre, Central Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Alexandra Sharland
- Transplantation Immunobiology Research Group, Faculty of Medicine and Health, Charles Perkins Centre, Central Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Masaru Nomura
- Department of Surgery, Keiwakai Ebetsu Hospital, Ebetsu, Japan
| | - Karren M Plain
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
| | - G Alexander Bishop
- Transplantation Immunobiology Research Group, Faculty of Medicine and Health, Charles Perkins Centre, Central Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Suzanne J Hodgkinson
- Transplantation Immunobiology Research Group, Faculty of Medicine and Health, Charles Perkins Centre, Central Clinical School, University of Sydney, Sydney, NSW, Australia
| | - Bruce M Hall
- Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia
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18
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Abstract
BACKGROUND Regulatory T (Treg) cell-based immunotherapies have been studied as potential cell-based modalities for promoting transplant survival. However, the efficacy of local delivery of Treg cells in corneal transplantation has not been fully elucidated. Herein, we investigated the kinetics of migration of subconjunctivally injected Treg cells and their role in promoting corneal allograft survival. METHODS GFPCD4CD25Foxp3 Treg cells were isolated from draining lymph nodes (DLNs) of GFP transgenic mice and were subconjunctivally injected to corneal allograft recipients. Next, Treg cells, conventional T cells (Tconv) or a combination of both was locally injected to graft recipients, and graft survival was determined by evaluating opacity scores for 10 weeks. Transplanted mice without treatment served as controls. The frequencies of major histocompatibility complex-IICD11b antigen-presenting cells, IFNγCD4 Th1 cells, and CD45 cells in the DLNs and cornea were evaluated at week 2 posttransplantation using flow cytometry. Expressions of IFNγ, IL-10 and TGF-β in the grafts were assessed using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS GFP Treg cells were detected in the ipsilateral cornea and DLNs of recipients 6 hours after injection. Subconjunctival injection of Treg cells significantly decreased the frequencies of mature antigen-presenting cells in the graft and DLNs, suppressed Th1 frequencies in DLNs, and inhibited CD45 cell infiltration to the graft. Finally, locally delivered Treg cells significantly reduced the expression of IFN-γ, enhanced the levels of IL-10 and TGF-β in the graft, and promoted long-term allograft survival. CONCLUSIONS Our study elucidates the kinetics of migration of locally delivered Treg cells and shows their role in suppressing host immune response against the allograft.
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19
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Akbarpour M, Bharat A. Lung Injury and Loss of Regulatory T Cells Primes for Lung-Restricted Autoimmunity. Crit Rev Immunol 2019; 37:23-37. [PMID: 29431077 DOI: 10.1615/critrevimmunol.2017024944] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lung transplantation is a life-saving therapy for several end-stage lung diseases. However, lung allografts suffer from the lowest survival rate predominantly due to rejection. The pathogenesis of alloimmunity and its role in allograft rejection has been extensively studied and multiple approaches have been described to induce tolerance. However, in the context of lung transplantation, dysregulation of mechanisms, which maintain tolerance against self-antigens, can lead to lung-restricted autoimmunity, which has been recently identified to drive the immunopathogenesis of allograft rejection. Indeed, both preexisting as well as de novo lung-restricted autoimmunity can play a major role in the development of lung allograft rejection. The three most widely studied lung-restricted self-antigens include collagen type I, collagen type V, and k-alpha 1 tubulin. In this review, we discuss the role of lung-restricted autoimmunity in the development of both early as well as late lung allograft rejection and recent literature providing insight into the development of lung-restricted autoimmunity through the dysfunction of immune mechanisms which maintain peripheral tolerance.
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Affiliation(s)
- Mahzad Akbarpour
- Division of Thoracic Surgery, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ankit Bharat
- Division of Thoracic Surgery, Department of Surgery; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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20
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Wang W, Zhao N, Li B, Gao H, Yan Y, Guo H. Inhibition of cardiac allograft rejection in mice using interleukin-35-modified mesenchymal stem cells. Scand J Immunol 2019; 89:e12750. [PMID: 30664805 DOI: 10.1111/sji.12750] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 01/14/2019] [Accepted: 01/16/2019] [Indexed: 02/03/2023]
Abstract
Interleukin-35 (IL-35) is a cytokine recently discovered to play a potent immunosuppressive role by intensifying the functions of regulatory T cells and inhibiting the proliferation and functions of T helper 1 and T helper 17 cells. Mesenchymal stem cells (MSCs) have recently emerged as promising candidates for cell-based immune therapy, and our previous study showed that IL-35 gene modification can effectively enhance the therapeutic effect of MSCs in vitro. In this study, we isolated adipose tissue-derived MSCs in vitro and infected them with lentiviral vectors overexpressing the IL-35 gene, thereby creating IL-35-MSCs. Subsequently, IL-35-MSCs were then injected into mice of the allogeneic heterotopic abdominal heart transplant model to determine their effect on allograft rejection. The results showed that IL-35-MSCs could continuously secrete IL-35 in vivo and in vitro, successfully alleviate allograft rejection and prolong graft survival. In addition, compared to MSCs, IL-35-MSCs showed a stronger immunosuppressive ability and further reduced the percentage of Th17 cells, increased the proportion of CD4+ Foxp3+ T cells, and regulated Th1/Th2 balance in heart transplant mice. These findings suggest that IL-35-MSCs have more advantages than MSCs in inhibiting graft rejection and may thus provide a new approach for inducing immune tolerance during transplantation.
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Affiliation(s)
- Wei Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Na Zhao
- Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Baozhu Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Haopeng Gao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Yongjia Yan
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
| | - Hao Guo
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China
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21
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Copsel SN, Lightbourn CO, Barreras H, Lohse I, Wolf D, Bader CS, Manov J, Kale BJ, Shah D, Brothers SP, Perez VL, Komanduri KV, Wahlestedt C, Levy RB. BET Bromodomain Inhibitors Which Permit Treg Function Enable a Combinatorial Strategy to Suppress GVHD in Pre-clinical Allogeneic HSCT. Front Immunol 2019; 9:3104. [PMID: 30733722 PMCID: PMC6353853 DOI: 10.3389/fimmu.2018.03104] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 12/17/2018] [Indexed: 01/09/2023] Open
Abstract
A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere in vivo with CD4+FoxP3+ regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig + IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules, such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6 → BALB/c) was performed using in vivo expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs + EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, in vivo EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses.
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Affiliation(s)
- Sabrina N Copsel
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Casey O Lightbourn
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Henry Barreras
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Ines Lohse
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.,Center for Therapeutic Innovation and Department of Psychiatry and Behavior Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Cameron S Bader
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - John Manov
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Brandon J Kale
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Devangi Shah
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Shaun P Brothers
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.,Center for Therapeutic Innovation and Department of Psychiatry and Behavior Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Victor L Perez
- Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Krishna V Komanduri
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.,Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Claes Wahlestedt
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.,Center for Therapeutic Innovation and Department of Psychiatry and Behavior Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States
| | - Robert B Levy
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United States.,Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.,Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United States.,Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States
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22
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LeGuern C, Germana S. On the elusive TCR specificity of thymic regulatory T cells. Am J Transplant 2019; 19:15-20. [PMID: 30378738 DOI: 10.1111/ajt.15165] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 10/16/2018] [Accepted: 10/20/2018] [Indexed: 01/25/2023]
Abstract
Therapies using thymus-derived regulatory T cells (Tregs) are promising strategies for preventing autoimmunity or graft rejection. The efficacy of these approaches is, however, contingent on a better understanding of Treg mode of action, especially about factors controlling their activation in vivo. Although key parameters of Treg suppression have been identified, little information is available on Treg activation in vivo via the TCR. In light of recent studies using TCR transgenic mouse models as well as unpublished data, we discuss evidence in support of the view that Treg TCR specificities are not necessarily highly diverse, that the accessibility of Treg selective antigens control Treg development, and that peptides derived from MHC class II (MHC-II) could be prevailing antigens involved in Treg selection. This novel perspective provides insights on Treg development as well as a conceptual basis to a significant contribution of MHC-II derived peptides in the shaping of the Treg TCR repertoire.
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Affiliation(s)
- Christian LeGuern
- Massachusetts General Hospital/Harvard Medical School - Center for Transplantation Sciences, Charlestown, Massachusetts
| | - Sharon Germana
- Massachusetts General Hospital/Harvard Medical School - Center for Transplantation Sciences, Charlestown, Massachusetts
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23
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Jeon YW, Lim JY, Im KI, Kim N, Nam YS, Song YJ, Cho SG. Enhancement of Graft-Versus-Host Disease Control Efficacy by Adoptive Transfer of Type 1 Regulatory T Cells in Bone Marrow Transplant Model. Stem Cells Dev 2018; 28:129-140. [PMID: 30381994 DOI: 10.1089/scd.2018.0113] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Interleukin (IL)-10-producing type 1 regulatory T (Tr1) cells, which are Foxp3-memory T lymphocytes, play important roles in peripheral immune tolerance. We investigated whether Tr1 cells exert immunoregulatory effects in a mouse model of acute graft-versus-host disease (GVHD). Mouse CD4+ T cells were induced to differentiate in vitro into Tr1 cells using vitamin D3 and dexamethasone, and these donor-derived Tr1 cells were infused on the day of bone marrow transplantation. The Tr1 cell-transferred group showed less weight-loss and a twofold higher survival rate than the GVHD group, together with markedly decreased histopathologic grades. It was associated with the expansion of CD4+IL-4+ type 2 T-helper (Th2) cells and CD4+CD25+Foxp3+ regulatory T (Treg) cells. Furthermore, Tr1 cells decreased the numbers of CD4+interferon-γ+ Th1 and CD4+IL-17+ Th17 cells. Recipient mice harbored some Foxp3+ Tregs due to adoptive transfer of Tr1 cells, together with the upregulated expression of costimulatory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and inducible T-cell costimulator (ICOS); however, the Treg cells did not show the plasticity. Therefore, adoptive Tr1 cell therapy may be effective against manifestations of GVHD, exert immunomodulatory effects in a manner dependent on CTLA-4 and ICOS, and induce differentiation of the transferred Tr1 cells into Foxp3+ Treg cells.
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Affiliation(s)
- Young-Woo Jeon
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea.,3 Lymphoma-Myeloma Center, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung-Yeon Lim
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Keon-Il Im
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Nayoun Kim
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Sun Nam
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yun-Jin Song
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- 1 Institute for Translational Research and Molecular Imaging, College of Medicine, The Catholic University of Korea, Seoul, Korea.,2 Laboratory of Immune Regulation, Convergent Research Consortium for Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea.,3 Lymphoma-Myeloma Center, Catholic Hematology Hospital, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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24
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Wolf D, Bader CS, Barreras H, Copsel S, Pfeiffer BJ, Lightbourn CO, Altman NH, Komanduri KV, Levy RB. Superior immune reconstitution using Treg-expanded donor cells versus PTCy treatment in preclinical HSCT models. JCI Insight 2018; 3:121717. [PMID: 30333311 DOI: 10.1172/jci.insight.121717] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/30/2018] [Indexed: 12/20/2022] Open
Abstract
Posttransplant cyclophosphamide (PTCy) has been found to be effective in ameliorating acute graft-versus-host disease (GVHD) in patients following allogeneic hematopoietic stem cell transplantation (aHSCT). Adoptive transfer of high numbers of donor Tregs in experimental aHSCT has shown promise as a therapeutic modality for GVHD regulation. We recently described a strategy for in vivo Treg expansion targeting two receptors: TNFRSF25 and CD25. To date, there have been no direct comparisons between the use of PTCy and Tregs regarding outcome and immune reconstitution within identical groups of transplanted mice. Here, we assessed these two strategies and found both decreased clinical GVHD and improved survival long term. However, recipients transplanted with Treg-expanded donor cells (TrED) exhibited less weight loss early after HSCT. Additionally, TrED recipients demonstrated less thymic damage, significantly more recent thymic emigrants, and more rapid lymphoid engraftment. Three months after HSCT, PTCy-treated and TrED recipients showed tolerance to F1 skin allografts and comparable immune function. Overall, TrED was found superior to PTCy with regard to weight loss early after transplant and initial lymphoid engraftment. Based on these findings, we speculate that morbidity and mortality after transplant could be diminished following TrED transplant into aHSCT recipients, and, therefore, that TrED could provide a promising clinical strategy for GVHD prophylaxis.
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Affiliation(s)
| | | | | | | | | | | | | | - Krishna V Komanduri
- Sylvester Comprehensive Cancer Center.,Department of Microbiology & Immunology.,Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Robert B Levy
- Sylvester Comprehensive Cancer Center.,Department of Microbiology & Immunology.,Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA
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25
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Li X, Meng Q, Zhang L. The Fate of Allogeneic Pancreatic Islets following Intraportal Transplantation: Challenges and Solutions. J Immunol Res 2018; 2018:2424586. [PMID: 30345316 PMCID: PMC6174795 DOI: 10.1155/2018/2424586] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/27/2018] [Indexed: 12/26/2022] Open
Abstract
Pancreatic islet transplantation as a therapeutic option for type 1 diabetes mellitus is gaining widespread attention because this approach can restore physiological insulin secretion, minimize the risk of hypoglycemic unawareness, and reduce the risk of death due to severe hypoglycemia. However, there are many obstacles contributing to the early mass loss of the islets and progressive islet loss in the late stages of clinical islet transplantation, including hypoxia injury, instant blood-mediated inflammatory reactions, inflammatory cytokines, immune rejection, metabolic exhaustion, and immunosuppression-related toxicity that is detrimental to the islet allograft. Here, we discuss the fate of intrahepatic islets infused through the portal vein and propose potential interventions to promote islet allograft survival and improve long-term graft function.
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Affiliation(s)
- Xinyu Li
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086 Heilongjiang Province, China
| | - Qiang Meng
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086 Heilongjiang Province, China
| | - Lei Zhang
- Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150086 Heilongjiang Province, China
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26
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Abstract
PURPOSE OF REVIEW The immunosuppressive agent cyclosporine was first reported to lower daily insulin dose and improve glycemic control in patients with new-onset type 1 diabetes (T1D) in 1984. While renal toxicity limited cyclosporine's extended use, this observation ignited collaborative efforts to identify immunotherapeutic agents capable of safely preserving β cells in patients with or at risk for T1D. RECENT FINDINGS Advances in T1D prediction and early diagnosis, together with expanded knowledge of the disease mechanisms, have facilitated trials targeting specific immune cell subsets, autoantigens, and pathways. In addition, clinical responder and non-responder subsets have been defined through the use of metabolic and immunological readouts. Herein, we review emerging T1D biomarkers within the context of recent and ongoing T1D immunotherapy trials. We also discuss responder/non-responder analyses in an effort to identify therapeutic mechanisms, define actionable pathways, and guide subject selection, drug dosing, and tailored combination drug therapy for future T1D trials.
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Affiliation(s)
- Laura M Jacobsen
- Department of Pediatrics, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Brittney N Newby
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, 1275 Center Drive, Biomedical Sciences Building J-589, Box 100275, Gainesville, FL, 32610, USA
| | - Daniel J Perry
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, 1275 Center Drive, Biomedical Sciences Building J-589, Box 100275, Gainesville, FL, 32610, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, 1275 Center Drive, Biomedical Sciences Building J-589, Box 100275, Gainesville, FL, 32610, USA
| | - Michael J Haller
- Department of Pediatrics, College of Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida Diabetes Institute, 1275 Center Drive, Biomedical Sciences Building J-589, Box 100275, Gainesville, FL, 32610, USA.
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27
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Walavalkar V, Adey DB, Laszik ZG, Jen KY. Severe Renal Allograft Rejection Resulting from Lenalidomide Therapy for Multiple Myeloma: Case Report. Transplant Proc 2018; 50:873-876. [PMID: 29661456 DOI: 10.1016/j.transproceed.2018.01.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 01/19/2018] [Indexed: 12/27/2022]
Abstract
Lenalidomide, a thalidomide analogue, is an immunomodulatory drug currently used as a chemotherapeutic agent in treating certain hematologic malignancies, including multiple myeloma. The antineoplastic effect of lenalidomide may be due to its ability to modulate different components of the immune system as well as its antiangiogenic, antiproliferative, and direct cytotoxic activity. Given its immunomodulatory effects, lenalidomide may potentially elicit unintended immune activity against allografts in solid organ transplant recipients. Here, we present a case of a renal transplant recipient who developed multiple myeloma after transplantation and was treated with the use of lenalidomide, which precipitated severe acute T-cell-mediated rejection. Lenalidomide was thought to be causative, and after cessation of the drug her renal function stabilized.
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Affiliation(s)
- V Walavalkar
- Department of Pathology, University of California, San Francisco, California
| | - D B Adey
- Division of Nephrology, University of California, San Francisco, California
| | - Z G Laszik
- Department of Pathology, University of California, San Francisco, California
| | - K-Y Jen
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, California.
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28
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Zhang AH, Yoon J, Kim YC, Scott DW. Targeting Antigen-Specific B Cells Using Antigen-Expressing Transduced Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2018; 201:1434-1441. [PMID: 30021767 DOI: 10.4049/jimmunol.1701800] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 06/27/2018] [Indexed: 01/23/2023]
Abstract
Controlling immune responses in autoimmunity and to biotherapeutics is an unmet need. In hemophilia, for example, up to one third of patients receiving therapeutic factor VIII (FVIII) infusions develop neutralizing Abs termed "inhibitors." To address this problem in a mouse model of hemophilia A, we used an Ag-specific regulatory T cell (Treg) approach in which we created a novel B cell-targeting chimeric receptor composed of an FVIII Ag domain linked with the CD28-CD3ζ transmembrane and signaling domains. We termed these "BAR" for B cell-targeting Ab receptors. CD4+CD25hiCD127low human Tregs were retrovirally transduced to express a BAR containing the immunodominant FVIII C2 or A2 domains (C2- and A2-BAR). Such BAR-Tregs specifically suppressed the recall Ab response of spleen cultures from FVIII-immunized mice in vitro and completely prevented anti-FVIII Ab development in response to FVIII immunization. Mechanistic studies with purified B cells and T cells from tolerized or control recipients demonstrated that the FVIII-specific B cells were directly suppressed or anergized, whereas the T cell response remained intact. Taken together, we report in this study a successful proof-of-principle strategy using Ag-expressing Tregs to directly target specific B cells, an approach which could be adapted to address other adverse immune responses as well.
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Affiliation(s)
- Ai-Hong Zhang
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
| | - Jeongheon Yoon
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
| | - Yong Chan Kim
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
| | - David W Scott
- Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814
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29
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Khan MA, Alanazi F, Ahmed HA, Vater A, Assiri AM, Broering DC. C5a Blockade Increases Regulatory T Cell Numbers and Protects Against Microvascular Loss and Epithelial Damage in Mouse Airway Allografts. Front Immunol 2018; 9:1010. [PMID: 29881374 PMCID: PMC5976734 DOI: 10.3389/fimmu.2018.01010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 04/23/2018] [Indexed: 12/15/2022] Open
Abstract
Microvascular injury during acute rejection has been associated with massive infiltration of CD4+ T effector cells, and the formation of complement products (C3a and C5a). Regulatory T cells (Tregs) are potent immunosuppressors of the adaptive immune system and have proven sufficient to rescue microvascular impairments. Targeting C5a has been linked with improved microvascular recovery, but its effects on the Treg and T effector balance is less well known. Here, we demonstrate the impact of C5a blockade on Treg induction and microvascular restoration in rejecting mouse airway allografts. BALB/c→C57BL/6 allografts were treated with a C5a-neutralizing l-aptamer (10 mg/kg, i.p. at d0 and every second day thereafter), and allografts were serially monitored for Treg infiltration, tissue oxygenation (tpO2), microvascular blood flow, and functional microvasculature between donor and recipients during allograft rejection. We demonstrated that C5a blocking significantly leads to enhanced presence of Tregs in the allograft, reinstates donor-recipient functional microvasculature, improves tpO2, microvascular blood flow, and epithelial repair, followed by an upregulation of IL-5, TGF-β, IL-10 vascular endothelial growth factor, and ANGPT1 gene expression, while it maintained a healthy epithelium and prevented subepithelial collagen deposition at d28 posttransplantation. Together, these data indicate that inhibition of C5a signaling has potential to preserve microvasculature and rescue allograft from a sustained hypoxic/ischemic phase, limits airway tissue remodeling through the induction of Treg-mediated immune tolerance. These findings may be useful in designing anti-C5a therapy in combination with existing immunosuppressive regimens to rescue tissue/organ rejection.
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Affiliation(s)
- Mohammad Afzal Khan
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Fatimah Alanazi
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hala Abdalrahman Ahmed
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | | | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
- Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Dieter Clemens Broering
- Organ Transplant Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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30
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Copsel S, Wolf D, Kale B, Barreras H, Lightbourn CO, Bader CS, Alperstein W, Altman NH, Komanduri KV, Levy RB. Very Low Numbers of CD4 + FoxP3 + Tregs Expanded in Donors via TL1A-Ig and Low-Dose IL-2 Exhibit a Distinct Activation/Functional Profile and Suppress GVHD in a Preclinical Model. Biol Blood Marrow Transplant 2018; 24:1788-1794. [PMID: 29751114 DOI: 10.1016/j.bbmt.2018.04.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Accepted: 04/23/2018] [Indexed: 11/25/2022]
Abstract
Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach that induces the marked expansion and selective activation of Tregs in vivo by targeting tumor necrosis factor receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Tregs to ameliorate GVHD and other disorders would be the generation of more potent Treg populations. Here we wanted to determine if very low doses of Tregs generated using the "2-pathway" stimulation protocol via TL1A-Ig fusion protein and low-dose IL-2 (targeting TNFRSF25 and CD25, respectively) could be used to regulate preclinical GVHD. Analysis of such 2-pathway expanded Tregs identified higher levels of activation and functional molecules (CD103, ICOS-1, Nrp-1, CD39, CD73, il-10, and tgfb1) versus unexpanded Tregs. Additionally, in vitro assessment of 2-pathway stimulated Tregs indicated enhanced suppressor activity. Notably, transplant of extremely low numbers of these Tregs (1:6 expanded Tregs/conventional T cells) suppressed GVHD after an MHC-mismatched aHSCT. Overall, these results demonstrate that 2-pathway stimulated CD4+ FoxP3+ Tregs were quantitatively and qualitatively more functionally effective than unexpanded Tregs. In total, the findings in this study support the notion that such 2-pathway stimulated Tregs may be useful for prevention of GVHD and ultimately promote more widespread application of aHSCT in the clinic.
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Affiliation(s)
- Sabrina Copsel
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida
| | - Brandon Kale
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Henry Barreras
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Casey O Lightbourn
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Cameron S Bader
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida
| | - Warren Alperstein
- Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, Florida
| | - Norman H Altman
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, Florida
| | - Krishna V Komanduri
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida
| | - Robert B Levy
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida; Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida; Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, Florida.
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31
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Kawai K, Uchiyama M, Hester J, Wood K, Issa F. Regulatory T cells for tolerance. Hum Immunol 2018; 79:294-303. [DOI: 10.1016/j.humimm.2017.12.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/16/2017] [Accepted: 12/26/2017] [Indexed: 12/29/2022]
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32
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Miao J, Zhu P. Functional Defects of Treg Cells: New Targets in Rheumatic Diseases, Including Ankylosing Spondylitis. Curr Rheumatol Rep 2018; 20:30. [PMID: 29663162 DOI: 10.1007/s11926-018-0729-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE OF REVIEW This study aims to review the advances of Treg cell biology, the functional defects of Treg cells, and the potential strategies for the experimental, preclinical or clinical application of Treg cell therapy in the context of autoimmune/immune-mediated rheumatic diseases. RECENT FINDINGS CD4+CD25+ regulatory T (Treg) cells are a phenotypically and functionally heterogeneous subset of lymphocytes that prevent a variety of autoimmune diseases. As in many autoimmune diseases, the functional defects of Treg cells are supposed to play relevant roles in the pathogenesis and development of systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, and other autoimmune/immune-mediated rheumatic diseases. Consequently, manipulation and modulation of Treg cells represent a potent strategy for therapeutic benefit in many such diseases. A further understanding of the functional defects of Treg cells in rheumatic diseases will contribute to find new targets and therapies in rheumatic diseases, including ankylosing spondylitis.
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Affiliation(s)
- Jinlin Miao
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, Shaanxi Province, People's Republic of China
| | - Ping Zhu
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, Shaanxi Province, People's Republic of China.
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33
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The ratio of circulating regulatory cluster of differentiation 4 T cells to endothelial progenitor cells predicts clinically significant acute rejection after heart transplantation. J Heart Lung Transplant 2018; 37:496-502. [DOI: 10.1016/j.healun.2017.10.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 09/27/2017] [Accepted: 10/18/2017] [Indexed: 11/23/2022] Open
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34
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Fujimoto H, Saito Y, Ohuchida K, Kawakami E, Fujiki S, Watanabe T, Ono R, Kaneko A, Takagi S, Najima Y, Hijikata A, Cui L, Ueki T, Oda Y, Hori S, Ohara O, Nakamura M, Saito T, Ishikawa F. Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1 + T Cells in Human Colorectal Cancer. THE JOURNAL OF IMMUNOLOGY 2018; 200:3291-3303. [PMID: 29581358 DOI: 10.4049/jimmunol.1701222] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 02/27/2018] [Indexed: 12/11/2022]
Abstract
Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8+ T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3+ Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.
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Affiliation(s)
- Hanae Fujimoto
- Department of Immune Regulation Research, Graduate School of Medical and Pharmaceutical Sciences, Chiba University, Chiba 260-0856, Japan.,Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Yoriko Saito
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Eiryo Kawakami
- RIKEN Medical Sciences Innovation Hub Program, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Saera Fujiki
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Takashi Watanabe
- Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Rintaro Ono
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Akiko Kaneko
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Shinsuke Takagi
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Yuho Najima
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Atsushi Hijikata
- Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Lin Cui
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takashi Ueki
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Department of Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Shohei Hori
- Laboratory for Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan; and
| | - Osamu Ohara
- Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.,Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takashi Saito
- Laboratory for Cell Signaling, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Fumihiko Ishikawa
- Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan;
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35
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Okamura T, Yamamoto K, Fujio K. Early Growth Response Gene 2-Expressing CD4 +LAG3 + Regulatory T Cells: The Therapeutic Potential for Treating Autoimmune Diseases. Front Immunol 2018. [PMID: 29535721 PMCID: PMC5834469 DOI: 10.3389/fimmu.2018.00340] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4+CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+CD25+ Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells. Lymphocyte activation gene 3 (LAG3) and CD49b are reliable cell surface markers for Tr1 cells. CD4+CD25−LAG3+ Tregs (LAG3+ Tregs) develop in the periphery and produce a large amount of IL-10. LAG3+ Tregs characteristically express the early growth response gene 2 (Egr2), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although Egr2 was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that Egr2 plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3+ Tregs. Intriguingly, forced expression of Egr2 converts naive CD4+ T cells into IL-10-producing Tregs that highly express LAG3. Among the four Egr gene family members, Egr3 is thought to compensate for the function of Egr2. Recently, we reported that LAG3+ Tregs suppress humoral immune responses via transforming growth factor β3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of Egr2 in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.
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Affiliation(s)
- Tomohisa Okamura
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Max Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Yamamoto
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Max Planck-The University of Tokyo Center for Integrative Inflammology, The University of Tokyo, Tokyo, Japan.,Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
| | - Keishi Fujio
- Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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36
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c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice. Sci Rep 2018; 8:3310. [PMID: 29459675 PMCID: PMC5818514 DOI: 10.1038/s41598-018-21477-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/05/2018] [Indexed: 02/06/2023] Open
Abstract
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1−/− but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1−/− Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1−/− Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1−/− Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1−/− but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.
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37
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Marshall GP, Cserny J, Perry DJ, Yeh WI, Seay HR, Elsayed AG, Posgai AL, Brusko TM. Clinical Applications of Regulatory T cells in Adoptive Cell Therapies. CELL & GENE THERAPY INSIGHTS 2018; 4:405-429. [PMID: 34984106 PMCID: PMC8722436 DOI: 10.18609/cgti.2018.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Interest in adoptive T-cell therapies has been ignited by the recent clinical success of genetically-modified T cells in the cancer immunotherapy space. In addition to immune targeting for malignancies, this approach is now being explored for the establishment of immune tolerance with regulatory T cells (Tregs). Herein, we will summarize the basic science and clinical results emanating from trials directed at inducing durable immune regulation through administration of Tregs. We will discuss some of the current challenges facing the field in terms of maximizing cell purity, stability and expansion capacity, while also achieving feasibility and GMP production. Indeed, recent advances in methodologies for Treg isolation, expansion, and optimal source materials represent important strides toward these considerations. Finally, we will review the emerging genetic and biomaterial-based approaches on the horizon for directing Treg specificity to augment tissue-targeting and regenerative medicine.
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Affiliation(s)
| | - Judit Cserny
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Daniel J Perry
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Wen-I Yeh
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Howard R Seay
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Ahmed G Elsayed
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA.,Department of Microbiology and Immunology, Faculty of Medicine, Mansoura University, Egypt
| | - Amanda L Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Todd M Brusko
- OneVax LLC, Sid Martin Biotechnology Institute, Alachua, Florida, USA.,Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
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38
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Won HY, Shin JH, Oh S, Jeong H, Hwang ES. Enhanced CD25 +Foxp3 + regulatory T cell development by amodiaquine through activation of nuclear receptor 4A. Sci Rep 2017; 7:16946. [PMID: 29208963 PMCID: PMC5717225 DOI: 10.1038/s41598-017-17073-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 11/21/2017] [Indexed: 01/10/2023] Open
Abstract
CD4+ T cells play key roles in the regulation of immune responses against pathogenic infectious antigens via development into effector T helper and induced regulatory T (iTreg) cells. Particularly, CD4+CD25+Foxp3+ iTreg cells are crucial for maintaining immune homeostasis and controlling inflammatory diseases. Anti-inflammatory drugs that enhance iTreg cell generation would be effective at preventing and treating inflammatory and autoimmune diseases. In this study, we examined whether anti-malarial and anti-arthritic amodiaquine (AQ) could affect iTreg cell development. Despite the anti-proliferative activity of AQ, AQ only moderately decreased iTreg cell proliferation but substantially increased IL-2 production by iTreg cells. Furthermore, AQ dose-dependently increased iTreg cell development and significantly upregulated iTreg cell markers including CD25. Interestingly, CD25 expression was decreased at later stages of iTreg cell development but was sustained in the presence of AQ, which was independent of IL-2 signaling pathway. AQ directly increased CD25 gene transcription by enhancing the DNA-binding and transcriptional activity of nuclear receptor 4 A. Most importantly, in vivo administration of AQ attenuated inflammatory colitis, resulted in the increased iTreg cells and decreased inflammatory cytokines. The ability of anti-malarial AQ to potentiate iTreg cell development makes it a promising drug for preventing and treating inflammatory and autoimmune diseases.
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MESH Headings
- Amodiaquine/pharmacology
- Animals
- Cell Proliferation/drug effects
- Colitis/drug therapy
- Colitis/etiology
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Forkhead Transcription Factors/metabolism
- Interleukin-2/metabolism
- Interleukin-2 Receptor alpha Subunit/genetics
- Interleukin-2 Receptor alpha Subunit/metabolism
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 1/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Receptors, Interleukin-2/metabolism
- Receptors, Steroid/genetics
- Receptors, Steroid/metabolism
- Receptors, Thyroid Hormone/genetics
- Receptors, Thyroid Hormone/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/physiology
- Transforming Growth Factor beta/pharmacology
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Affiliation(s)
- Hee Yeon Won
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Ji Hyun Shin
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Sera Oh
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Hana Jeong
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea
| | - Eun Sook Hwang
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea.
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39
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Kishore M, Cheung KCP, Fu H, Bonacina F, Wang G, Coe D, Ward EJ, Colamatteo A, Jangani M, Baragetti A, Matarese G, Smith DM, Haas R, Mauro C, Wraith DC, Okkenhaug K, Catapano AL, De Rosa V, Norata GD, Marelli-Berg FM. Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity 2017; 47:875-889.e10. [PMID: 29166588 PMCID: PMC5714502 DOI: 10.1016/j.immuni.2017.10.017] [Citation(s) in RCA: 180] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 06/30/2017] [Accepted: 10/26/2017] [Indexed: 12/27/2022]
Abstract
Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene-leading to increased GCK activity-had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration.
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Affiliation(s)
- Madhav Kishore
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Kenneth C P Cheung
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Hongmei Fu
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Fabrizia Bonacina
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy
| | - Guosu Wang
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - David Coe
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Eleanor J Ward
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Alessandra Colamatteo
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy
| | - Maryam Jangani
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Andrea Baragetti
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy
| | - Giuseppe Matarese
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," Naples 80131, Italy
| | - David M Smith
- Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, Cambridgeshire CB40WG, UK
| | - Robert Haas
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - Claudio Mauro
- William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK
| | - David C Wraith
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Klaus Okkenhaug
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK
| | - Alberico L Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy; IRCCS Multimedica Hospital, Milan 20138, Italy
| | - Veronica De Rosa
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy
| | - Giuseppe D Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
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40
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Passerini L, Bacchetta R. Forkhead-Box-P3 Gene Transfer in Human CD4 + T Conventional Cells for the Generation of Stable and Efficient Regulatory T Cells, Suitable for Immune Modulatory Therapy. Front Immunol 2017; 8:1282. [PMID: 29075264 PMCID: PMC5643480 DOI: 10.3389/fimmu.2017.01282] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/25/2017] [Indexed: 12/17/2022] Open
Abstract
The development of novel approaches to control immune responses to self- and allogenic tissues/organs represents an ambitious goal for the management of autoimmune diseases and in transplantation. Regulatory T cells (Tregs) are recognized as key players in the maintenance of peripheral tolerance in physiological and pathological conditions, and Treg-based cell therapies to restore tolerance in T cell-mediated disorders have been designed. However, several hurdles, including insufficient number of Tregs, their stability, and their antigen specificity, have challenged Tregs clinical applicability. In the past decade, the ability to engineer T cells has proven a powerful tool to redirect specificity and function of different cell types for specific therapeutic purposes. By using lentivirus-mediated gene transfer of the thymic-derived Treg transcription factor forkhead-box-P3 (FOXP3) in conventional CD4+ T cells, we converted effector T cells into Treg-like cells, endowed with potent in vitro and in vivo suppressive activity. The resulting CD4FOXP3 T-cell population displays stable phenotype and suppressive function. We showed that this strategy restores Treg function in T lymphocytes from patients carrying mutations in FOXP3 [immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)], in whom CD4FOXP3 T cell could be used as therapeutics to control autoimmunity. Here, we will discuss the potential advantages of using CD4FOXP3 T cells for in vivo application in inflammatory diseases, where tissue inflammation may undermine the function of natural Tregs. These findings pave the way for the use of engineered Tregs not only in IPEX syndrome but also in autoimmune disorders of different origin and in the context of stem cell and organ transplantation.
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Affiliation(s)
- Laura Passerini
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rosa Bacchetta
- Department of Stem Cell Transplantation and Regenerative Medicine, Division of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
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41
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Mohr F, Fischer JC, Nikolaus M, Stemberger C, Dreher S, Verschoor A, Haas T, Poeck H, Busch DH. Minimally manipulated murine regulatory T cells purified by reversible Fab Multimers are potent suppressors for adoptive T-cell therapy. Eur J Immunol 2017; 47:2153-2162. [DOI: 10.1002/eji.201747137] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 07/13/2017] [Accepted: 08/08/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Fabian Mohr
- Institute for Medical Microbiology; Immunology and Hygiene; Technische Universität München (TUM); Munich Germany
| | - Julius Clemens Fischer
- Klinik und Poliklinik für Innere Medizin III; Klinikum Rechts der Isar; TUM; Munich Germany
| | - Marc Nikolaus
- Institute for Medical Microbiology; Immunology and Hygiene; Technische Universität München (TUM); Munich Germany
| | - Christian Stemberger
- Focus Group “Clinical Cell Processing and Purification”; Institute for Advanced Study, TUM; Munich Germany
- Juno Cell Therapeutics; formerly Stage Cell Therapeutics; Munich Germany
| | - Stefan Dreher
- Focus Group “Clinical Cell Processing and Purification”; Institute for Advanced Study, TUM; Munich Germany
- Juno Cell Therapeutics; formerly Stage Cell Therapeutics; Munich Germany
| | - Admar Verschoor
- Institute for Medical Microbiology; Immunology and Hygiene; Technische Universität München (TUM); Munich Germany
- Institut für Systemische Entzündungsforschung; Universität zu Lübeck; Lübeck Germany
| | - Tobias Haas
- Institute for Medical Microbiology; Immunology and Hygiene; Technische Universität München (TUM); Munich Germany
- Klinik und Poliklinik für Innere Medizin III; Klinikum Rechts der Isar; TUM; Munich Germany
| | - Hendrik Poeck
- Klinik und Poliklinik für Innere Medizin III; Klinikum Rechts der Isar; TUM; Munich Germany
| | - Dirk H. Busch
- Institute for Medical Microbiology; Immunology and Hygiene; Technische Universität München (TUM); Munich Germany
- Focus Group “Clinical Cell Processing and Purification”; Institute for Advanced Study, TUM; Munich Germany
- National Center for Infection Research (DZIF); Munich Germany
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42
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Akimova T, Zhang T, Negorev D, Singhal S, Stadanlick J, Rao A, Annunziata M, Levine MH, Beier UH, Diamond JM, Christie JD, Albelda SM, Eruslanov EB, Hancock WW. Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. JCI Insight 2017; 2:94075. [PMID: 28814673 DOI: 10.1172/jci.insight.94075] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 07/19/2017] [Indexed: 12/15/2022] Open
Abstract
Experimental data indicate that FOXP3+ Tregs can markedly curtail host antitumor immune responses, but the properties of human intratumoral Tregs are still largely unknown, in part due to significant methodologic problems. We studied the phenotypic, functional, epigenetic, and transcriptional features of Tregs in 92 patients with non-small-cell lung cancer, comparing the features of Tregs within tumors versus corresponding blood, lung, and lymph node samples. Intratumoral Treg numbers and suppressive function were significantly increased compared with all other sites but did not display a distinctive phenotype by flow cytometry. However, by undertaking simultaneous evaluation of mRNA and protein expression at the single-cell level, we demonstrated that tumor Tregs have a phenotype characterized by upregulated expression of FOXP3 mRNA and protein as well as significantly increased expression of EOS, IRF4, SATB1, and GATA1 transcription factor mRNAs. Expression of these "Treg-locking" transcription factors was positively correlated with levels of FOXP3 mRNA, with highest correlations for EOS and SATB1. EOS had an additional, FOXP3 mRNA-independent, positive correlation with FOXP3 protein in tumor Tregs. Our study identifies distinctive features of intratumoral Tregs and suggests that targeting Treg-locking transcription factors, especially EOS, may be of clinical importance for antitumor Treg-based therapy.
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Affiliation(s)
- Tatiana Akimova
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tianyi Zhang
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dmitri Negorev
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sunil Singhal
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jason Stadanlick
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Abhishek Rao
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Michael Annunziata
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Matthew H Levine
- Department of Surgery, Penn Transplant Institute, Hospital of the University of Pennsylvania and University of Pennsylvania, Philadelphia, Pennsylvania, USA. Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Ulf H Beier
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joshua M Diamond
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and
| | - Jason D Christie
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and.,Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Steven M Albelda
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and
| | - Evgeniy B Eruslanov
- Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Wayne W Hancock
- Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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43
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Zwang NA, Leventhal JR. Cell Therapy in Kidney Transplantation: Focus on Regulatory T Cells. J Am Soc Nephrol 2017; 28:1960-1972. [PMID: 28465379 DOI: 10.1681/asn.2016111206] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Renal transplantation is the renal replacement modality of choice for suitable candidates with advanced CKD or ESRD. Prevention of rejection, however, requires treatment with nonspecific pharmacologic immunosuppressants that carry both systemic and nephrologic toxicities. Use of a patient's own suppressive regulatory T cells (Tregs) is an attractive biologic approach to reduce this burden. Here, we review the immunologic underpinnings of Treg therapy and technical challenges to developing successful cell therapy. These issues include the selection of appropriate Treg subsets, ex vivo Treg expansion approaches, how many Tregs to administer and when, and how to care for patients after Treg administration.
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Affiliation(s)
| | - Joseph R Leventhal
- Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, Illinois
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44
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Regulatory immune cells and functions in autoimmunity and transplantation immunology. Autoimmun Rev 2017; 16:435-444. [DOI: 10.1016/j.autrev.2017.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 01/26/2017] [Indexed: 12/15/2022]
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45
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Ye Q, Liu L, Wu Y, Yeh F, Li W, Tseng L, Ho C. Intralipid ® attenuates acute cardiac allograft rejection in relation to promoting CD4 + CD25 + Foxp3 + regulatory T-cells and inhibiting toll-like receptor 4 expression. TRANSPLANTATION REPORTS 2017. [DOI: 10.1016/j.tpr.2017.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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46
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Wolf D, Barreras H, Bader CS, Copsel S, Lightbourn CO, Pfeiffer BJ, Altman NH, Podack ER, Komanduri KV, Levy RB. Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2017; 23:757-766. [PMID: 28219835 DOI: 10.1016/j.bbmt.2017.02.013] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/16/2017] [Indexed: 01/23/2023]
Abstract
Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.
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Affiliation(s)
- Dietlinde Wolf
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida
| | - Henry Barreras
- Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Cameron S Bader
- Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Sabrina Copsel
- Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Casey O Lightbourn
- Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Brent J Pfeiffer
- Department of Pediatrics, University of Miami, Miller School of Medicine, Miami, Florida
| | - Norman H Altman
- Department of Pathology and Laboratory Medicine, University of Miami, Miller School of Medicine, Miami, Florida
| | - Eckhard R Podack
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Krishna V Komanduri
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Robert B Levy
- Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida; Department of Microbiology and Immunology, University of Miami, Miller School of Medicine, Miami, Florida; Department of Ophthalmology, University of Miami, Miller School of Medicine, Miami, Florida.
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47
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Khan MA. T regulatory cell mediated immunotherapy for solid organ transplantation: A clinical perspective. Mol Med 2017; 22:892-904. [PMID: 27878210 PMCID: PMC5319206 DOI: 10.2119/molmed.2016.00050] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022] Open
Abstract
T regulatory cells (Tregs) play a vital role in suppressing heightened immune responses, and thereby promote a state of immunological tolerance. Tregs modulate both innate and adaptive immunity, which make them a potential candidate for cell-based immunotherapy to suppress uncontrolled activation of graft specific inflammatory cells and their toxic mediators. These grafts specific inflammatory cells (T effector cells) and other inflammatory mediators (Immunoglobulins, active complement mediators) are mainly responsible for graft vascular deterioration followed by acute/chronic rejection. Treg mediated immunotherapy is under investigation to induce allospecific tolerance in various ongoing clinical trials in organ transplant recipients. Treg immunotherapy is showing promising results but the key issues regarding Treg immunotherapy are not yet fully resolved including their mechanism of action, and specific Treg cell phenotype responsible for a state of tolerance. This review highlights the involvement of various subsets of Tregs during immune suppression, novelty of Tregs functions, effects on angiogenesis, emerging technologies for effective Treg expansion, plasticity and safety associated with clinical applications. Altogether this information will assist in designing single/combined Treg mediated therapies for successful clinical trials in solid organ transplantations.
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Affiliation(s)
- Mohammad Afzal Khan
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia 11211
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48
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Bender C, Christen S, Scholich K, Bayer M, Pfeilschifter JM, Hintermann E, Christen U. Islet-Expressed CXCL10 Promotes Autoimmune Destruction of Islet Isografts in Mice With Type 1 Diabetes. Diabetes 2017; 66:113-126. [PMID: 27797910 DOI: 10.2337/db16-0547] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 10/21/2016] [Indexed: 11/13/2022]
Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells in the pancreas. Thereby, the chemokine CXC-motif ligand 10 (CXCL10) plays an important role in the recruitment of autoaggressive lymphocytes to the islets of Langerhans. Transplantation of isolated islets as a promising therapy for T1D has been hampered by early graft rejection. Here, we investigated the influence of CXCL10 on the autoimmune destruction of islet isografts using RIP-LCMV mice expressing a lymphocytic choriomeningitis virus (LCMV) protein in the β-cells. RIP-LCMV islets express CXCL10 after isolation and maintain CXCL10 production after engraftment. Thus, we isolated islets from either normal or CXCL10-deficient RIP-LCMV mice and transferred them under the kidney capsule of diabetic RIP-LCMV mice. We found that the autoimmune destruction of CXCL10-deficient islet isografts was significantly reduced. The autoimmune destruction was also diminished in mice administered with an anti-CXCL10 antibody. The persistent protection from autoimmune destruction was paralleled by an increase in FoxP3+ regulatory T cells within the cellular infiltrates around the islet isografts. Consequently, CXCL10 might influence the cellular composition locally in the islet graft, thereby playing a role in the autoimmune destruction. CXCL10 might therefore constitute a potential therapeutic target to prolong islet graft survival.
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Affiliation(s)
- Christine Bender
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Selina Christen
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Klaus Scholich
- Institute for Clinical Pharmacology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Monika Bayer
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Josef M Pfeilschifter
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Edith Hintermann
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Urs Christen
- Institute for Pharmacology and Toxicology, Pharmazentrum Frankfurt/Center for Drug Research, Development, and Safety (ZAFES), Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
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49
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Berges C, Kerkau T, Werner S, Wolf N, Winter N, Hünig T, Einsele H, Topp MS, Beyersdorf N. Hsp90 inhibition ameliorates CD4 + T cell-mediated acute Graft versus Host disease in mice. IMMUNITY INFLAMMATION AND DISEASE 2016; 4:463-473. [PMID: 27980780 PMCID: PMC5134726 DOI: 10.1002/iid3.127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 08/18/2016] [Accepted: 08/21/2016] [Indexed: 11/22/2022]
Abstract
Introduction For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition. Conclusions Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.
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Affiliation(s)
- Carsten Berges
- Department of Internal Medicine II Division of Hematology University Hospital Würzburg Würzburg Germany
| | - Thomas Kerkau
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Sandra Werner
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Nelli Wolf
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Nadine Winter
- Department of Internal Medicine II Division of Hematology University Hospital Würzburg Würzburg Germany
| | - Thomas Hünig
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
| | - Hermann Einsele
- Department of Internal Medicine II Division of Hematology University Hospital Würzburg Würzburg Germany
| | - Max S Topp
- Department of Internal Medicine II Division of Hematology University Hospital Würzburg Würzburg Germany
| | - Niklas Beyersdorf
- Institute for Virology and Immunobiology University of Würzburg Würzburg Germany
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50
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