Role for exosomes with self-antigens and immune regulatory molecules in allo- and auto-immunity leading to chronic immune injury following murine kidney transplantation |
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| Institution: | 1. Norton Thoracic Institute, St. Joseph''s Hospital and Medical Center, Phoenix, AZ, United States of America;2. Department of Medicine, Mayo Clinic, Phoenix, AZ, United States of America;3. Department of Pathology, Yale School of Medicine, New Haven, CT, United States of America;1. Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan;2. Department of Hematology, Sasebo City General Hospital, Sasebo, Japan;3. Department of Hematology, Nagasaki University Hospital, Nagasaki, Japan;4. Department of Hematology, National Hospital Organization Nagasaki Medical Center, Omura, Japan;5. Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan;6. Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan;1. Neurological Surgery Department, University of São Paulo, School of Medicine, São Paulo, Brazil;2. Organ Procurement Organization, Hospital das Clínicas, University of São Paulo, School of Medicine, São Paulo, Brazil;3. Gastroenterology Department, University of São Paulo, School of Medicine, São Paulo, Brazil;4. Medical Science Department, Nove de Julho University, São Paulo, Brazil;5. Cardiopneumology Department, University of São Paulo, School of Medicine, São Paulo, Brazil;6. School of Nursing of the University of São Paulo, São Paulo, Brazil;1. Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India;2. Department of Urology Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India;1. Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices civils de Lyon, Lyon, France;2. Université Claude Bernard Lyon 1, Lyon, France;3. Service d''hépatologie et de Transplantation Hépatique, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France;4. Service des Maladies de l''Appareil Digestif, Hôpital Claude Huriez, CHRU Lille, Lille, France;5. Centre Hépato-Biliaire, Hôpital Paul Brousse, AP-HP, Villejuif, France;6. Département de Néphrologie et Transplantation d''Organes, CHU Rangueil, Toulouse, France;1. Medical Sciences Division, University of Oxford, Oxford, UK;2. Department of Surgery, University of Chicago, Chicago, IL, USA;3. Department of Medicine, Mount Auburn Hospital, Cambridge, MA, USA;4. Harvard Medical School, Boston, MA, USA;5. British Heart Foundation Centre of Excellence, King''s College London, London, UK;6. Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, UK;7. Imperial Vascular Unit, Imperial College Healthcare NHS Trust, London, UK;1. Department of Renal Surgery and Transplantation, Jichi Medical University Hospital, Tochigi, Japan;2. Department of Orthopaedics, Teikyo University School of Medicine, Tokyo, Japan;3. Oku medical clinic, Osaka, Japan;4. Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan |
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| Abstract: | ObjectiveAntibodies against donor human leukocyte antigen are a risk factor for chronic immune injury (CII) following renal transplantation; however, it is often not detectable. The main goal of this study is to gain new insights into the kinetics of exosome release and content in sensitized vs non-sensitized recipients. Towards this, we investigated the role for circulating exosomes with allo and self-antigens as well as immunoregulatory molecules in the development of CII and acute rejection.MethodsUsing murine kidney allograft rejection models, we investigated the role of exosomes on immune responses leading to allo- and auto-immunity to self-antigens resulting in rejection. Exosomes were analyzed for kidney self-antigens (Collagen-IV, fibronectin, angiotensin II receptor type 1), and immune-regulatory molecules (PD-L1, CD73) using western blot. Antibodies to donor MHC in serum samples were detected by immunofluorescence, self-antigens by enzyme-linked immunosorbent assay and kidney tissue infiltrating cells were determined by immunohistochemistry.ResultsBALB/c; H2d to C57BL/6; H2b renal transplantation (BALB/c), resulted in tubulitis and cellular infiltration by day 14, suggestive of acute inflammation, that was self-limiting with functioning graft. This contributed to CII on post-transplant day >100, which was preceded by induction of exosomes with donor and self-antigens leading to antibodies and immune-regulatory molecules. The absence of acute rejection in this allogenic transplant model is likely due to the induction of splenic and, graft-infiltrating CD4 + FoxP3+ T regulatory cells. In contrast, prior sensitization by skin graft followed by kidney transplantation induced antibodies to MHC and self-antigens leading to acute rejection.ConclusionWe demonstrate a pivotal role for induction of exosomes with immune-regulatory molecules, allo- and auto-immunity to self-antigens leading to chronic immune injury following murine kidney transplantation. |
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