Pre-clinical results of porcine islet re-transplantation after first porcine islet transplantation in rhesus monkeys
Jong-Min Kim1,3,4, So-Hee Hong1,2,3,5, Jun-Seop Shin1,3,4, Byoung-Hoon Min1,3,4, Jiyeon Kim2,3, Eung Soo Hwang1,2,3, Hee-Jung Kang1,6, Chung-Gyu Park1,2,3,4,5.
1Xenotransplantation Research Center, Seoul National University, College of Medicine, Seoul, Korea; 2Department of Microbiology and Immunology, Seoul National University, College of Medicine, Seoul, Korea; 3Institute of Endemic Diseases, Seoul National University, College of Medicine, Seoul, Korea; 4Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea; 5Department of Biomedical Sciences, Seoul National University, College of Medicine, Seoul, Korea; 6Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, Korea
Purpose: Allo-islet transplantation is an effective therapy for selected patients with type 1 diabetes with labile glycemic control and hypoglycemic unawareness. However, due to donor organ shortage, porcine islet transplantation has been highlighted as an alternative. Porcine islets are considered to be the best-matching implantable candidates for clinical application based on recent progress in nonhuman primate pre-clinical studies. Re-transplantation of porcine islet might be considered due to faster rejection of xeno-islet transplantation compared to allo-islet transplantation. Hence, in this study, we aimed to confirm whether sensitization of porcine islet might influence subsequent re-transplantation of porcine islet with consideration of graft survival in rhesus monkeys.
Methods: Three healthy rhesus monkeys were recipients of porcine islet transplantation (55,600~100,000 IEQ/kg). First immunosuppressive regimen is ATG, humira, anakinra, IVIg, tocilizumab (+/-), tacrolimus (+/-), and Treg (+/-) for induction, and belimumab, sirolimus and tofacitinib for maintenance therapy. When the blood glucose level increased after transplantation, porcine islets (49,000~100,000 IEQ/kg) were infused. Immunosuppressive regimen of re-transplantation consisted of humira, anakinra, IVIg, and tocilizumab for induction, and belimumab, sirolimus and tofacitinib for maintenance therapy. Graft survival days were defined as the day on which the serum porcine C-peptide fell below 0.15 ng/ml.
Results: The exogenous insulin dose were significantly decreased compared to those dose at diabetes mellitus after both transplantations. Survival days after first transplantation were >172, >438, and 406. The rhesus CMV copy numbers maintained low level during the experiment period.
Conclusions: These results suggest that clinical application of porcine islet re-transplantation when grafted porcine islet is not sufficient to control blood glucose level is likely to maintain graft function without acute rejection and to prolong the graft survival.
This study was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (Project No. HI13C0954) and partly the “Cooperative Research Program for Agriculture Science and Technology Development (Project No. PJ01345302)” Rural Development Administration, Republic of Korea. .
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