title: Failure of transplantation tolerance induction by autologous regulatory T cells in the pig-to-non-human primate islet xenotransplantation model.
abstract: Islet allotransplantation is a promising way to treat some type 1 diabetic (T1D) patients with frequent hypoglycemic unawareness, and islet xenotransplantation is emerging to overcome the problem of donor organ shortage. Our recent study showing reproducible long-term survival of porcine islets in non-human primates (NHPs) allows us to examine whether autologous regulatory T-cell (Treg) infusion at peri-transplantation period would induce transplantation tolerance in xenotransplantation setting.
  
  
  
  Two diabetic rhesus monkeys were transplanted with porcine islets from wild-type adult Seoul National University (SNU) miniature pigs with immunosuppression by anti-thymoglobulin (ATG), cobra venom factor, anti-CD154 monoclonal antibody (mAb), and sirolimus. CD4(+) CD25(high) CD127(low) autologous regulatory T cells from the recipients were isolated, ex vivo expanded, and infused at the peri-transplantation period. Blood glucose and porcine C-peptide from the recipients were measured up to 1000 days. Maintenance immunosuppressants including a CD40-CD154 blockade were deliberately discontinued to confirm whether transplantation tolerance was induced by adoptively transferred Tregs.
  
  
  
  After pig islet transplantation via portal vein, blood glucose levels of diabetic recipients became normalized and maintained over 6 months while in immunosuppressive maintenance with a CD40-CD154 blockade and sirolimus. However, the engrafted pig islets in the long-term period were fully rejected by activated immune cells, particularly T cells, when immunosuppressants were stopped, showing a failure of transplantation tolerance induction by autologous Tregs.
  
  
  
  Taken together, autologous Tregs infused at the peri-transplantation period failed to induce transplantation tolerance in pig-to-NHP islet xenotransplantation setting.
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jun-Seop
authors.identifier: 0000-0001-5142-2818
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Byoung-Hoon
authors.initials: BH
authors.lastname: Min
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Il Hee
authors.initials: IH
authors.lastname: Yoon
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Hyun Je
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jae Yool
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: National Medical Center, Seoul, Korea.
authors.forename: Dong-Gyun
authors.initials: DG
authors.lastname: Lim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jongwon
authors.initials: J
authors.lastname: Ha
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Myong-Ji Hospital, Koyang-si, Kyeonggi-do, Korea.
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation; D011323:Primates; D013552:Swine; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D007166:Immunosuppressive Agents
keywords: Tregs; non-human primates; pig islet transplantation