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Intraportal Transplantation of Pancreatic Islets in Mouse Model
Published on: May 5, 2018
JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys
Jong-Min Kim1,2,3, Jun-Seop Shin1,2,3,4, Byoung-Hoon Min1,2,3
1Xenotransplantation Research Center, Seoul National University College of Medicine , 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.
Insights
Janus kinase 3 (JAK3) inhibitor tofacitinib shows promise as a safer alternative to calcineurin inhibitors (CNIs) in islet transplantation. This study demonstrates its efficacy in nonhuman primates, potentially improving outcomes for type 1 diabetes patients.
Area of Science:
- Immunology
- Transplantation Biology
- Endocrinology
Background:
- Islet transplantation effectively manages type 1 diabetes but relies on calcineurin inhibitors (CNIs) with significant toxicity.
- CNIs like tacrolimus cause beta-cell and kidney damage, necessitating safer immunosuppressive alternatives.
- Developing alternative immunosuppression is crucial for improving the long-term success and safety of islet transplantation.
Purpose of the Study:
- To evaluate the efficacy and safety of a Janus kinase 3 (JAK3) inhibitor, tofacitinib, as a replacement for tacrolimus in an immunosuppression regimen.
- To assess the potential of JAK3 inhibition in preventing graft rejection and maintaining glycemic control in a nonhuman primate model of islet transplantation.
- To determine if JAK3 inhibitor-based immunosuppression can achieve similar potency to CNIs with an improved safety profile.
Main Methods:
- Utilized a streptozotocin (STZ)-induced diabetic cynomolgus nonhuman primate (NHP) model.
- Performed MHC-mismatched allogeneic islet transplantation.
- Administered a JAK3 inhibitor-based immunosuppression regimen (CIT07) as an alternative to tacrolimus.
- Monitored glycemic control via blood glucose levels and islet graft survival via serum C-peptide concentration.
- Assessed cellular and humoral immune responses and screened for viral reactivation (CMV) and posttransplant lymphoproliferative disease (PTLD).
Main Results:
- Islet transplantation led to rapid stabilization of blood glucose levels.
- Median islet graft survival was 98 days, with maximal survival exceeding 330 days in some subjects.
- JAK3 inhibitor-based immunosuppression effectively suppressed cellular and humoral immune responses.
- No serious infections or PTLD were observed, despite intermittent increases in cytomegalovirus (CMV) genome copy number.
- The JAK3 inhibitor demonstrated potential as a safe and effective alternative to tacrolimus.
Conclusions:
- JAK3 inhibitor tofacitinib can successfully replace tacrolimus in the CIT07 immunosuppression regimen for NHP islet transplantation.
- This approach offers a potentially safer alternative to CNIs, mitigating beta-cell and nephrotoxicity.
- The findings suggest that JAK3 inhibitors could be a valuable component of future human allogeneic islet transplantation protocols.
- Further research into JAK3 inhibitor-based immunosuppression is warranted for clinical application in type 1 diabetes treatment.
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