title: Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets.
abstract: Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin-induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy.
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: J S
authors.initials: JS
authors.lastname: Shin
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: J M
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: J S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: B H
authors.initials: BH
authors.lastname: Min
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: Y H
authors.initials: YH
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.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Jang
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: I H
authors.initials: IH
authors.lastname: Yoon
authors.affiliation: Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: E S
authors.initials: ES
authors.lastname: Hwang
authors.affiliation: National Medical Centre, Seoul, Korea.
authors.forename: D G
authors.initials: DG
authors.lastname: Lim
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: W W
authors.initials: WW
authors.lastname: Lee
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Ha
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: K C
authors.initials: KC
authors.lastname: Jung
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Park
authors.affiliation: Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.|Myong-Ji Hospital, Koyang-si, Kyeonggi-do, Korea.
authors.forename: S J
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 College of Medicine, Seoul, Korea.
authors.forename: C G
authors.initials: CG
authors.lastname: Park
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000601:surgery*; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D008253:Macaca mulatta; D008297:Male; D020123:Sirolimus / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D013552:Swine; D019172:Transplantation Conditioning / Q000379:methods*; D014183:Transplantation, Heterologous
chemical_list: D020123:Sirolimus
keywords: Animal models: nonhuman primate; diabetes: type 1; immunosuppressive regimens