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Islets. 2019;11(5):119-128. doi: 10.1080/19382014.2019.1650580. Epub 2019 Sep 4.

JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys.

Kim JM1,2,3, Shin JS1,2,3,4, Min BH1,2,3, Kang SJ1,2,4, Yoon IH1,2,4, Chung H1,2,4, Kim J1,2,4, Hwang ES1,2,4, Ha J5, Park CG1,2,3,4,6.

Author information

1
Xenotransplantation Research Center, Seoul National University College of Medicine , Seoul , Korea.
2
Institute of Endemic Diseases, Seoul National University College of Medicine , Seoul , Korea.
3
Cancer Research Institute, Seoul National University College of Medicine , Seoul , Korea.
4
Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul , Korea.
5
Department of Surgery, Seoul National University College of Medicine , Seoul , Korea.
6
Biomedical Research Institute, Seoul National University Hospital , Seoul, Korea.

Abstract

Islet transplantation is efficacious to prevent severe hypoglycemia and glycemic liability of selected patients of type 1 diabetes. However, since calcineurin inhibitor (CNI) causes β-cell and nephrotoxicity, alternative drug(s) with similar potency and safety profile to CNI will be highly desirable. Here we tested whether JAK3 inhibitor, tofacitinib could be used instead of tacrolimus in CIT07 immunosuppression regimen in cynomolgus nonhuman primate (NHP) model. Five independent streptozotocin (STZ)-induced diabetic monkeys were transplanted with MHC-mismatched allogeneic islets and three animals were further re-transplanted upon insufficient glycemic control or early islet graft rejection. After islet transplantation, blood glucose levels were quickly stabilized and maximal islet graft survival as measured by serum C-peptide concentration was >330, 98, >134, 31, or 22 days, respectively, after transplantation (median survival day; 98 days). Cellular and humoral immune responses were efficiently suppressed by JAK3 inhibitor-based immunosuppression during the follow-up periods. Although intermittent increases of the genome copy number of cynomolgus cytomegalovirus (CMV) were detected by quantitative real-time PCR analyses, serious infections or posttransplant lymphoproliferative disease (PTLD) was not found in all animals. Taken together, we have shown that JAK3 inhibitor could be used in replacement of tacrolimus in a highly translatable NHP islet transplantation model and these results suggest that JAK3 inhibitor will be potentially incorporated in human allogeneic islet transplantation.

KEYWORDS:

Calcineurin inhibitor; Islet transplantation; JAK3 inhibitor; NHP

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