Pre-Clinical Results of Islet Allo-Transplantation Using JAK Inhibitor as Replacement for Tacrolimus Widely Used Immunosuppressive Drug in Islet Transplantation in Cynomolgus Monkeys

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Abstract

Introduction

Islet transplantation is an effective therapy for selected patients with type 1 diabetes with labile glycemic control and hypoglycemic unawareness. Although tacrolimus has been effectively used effectively in islet transplantation field, it has been well known that it canto exert a diabetogenic effect. Recently, tofacitinib (a janus Janus kinase inhibitor (JAKi) which, was approved for treatment of rheumatoid arthritis) has been shown that it isto be effective in phase 3 clinical trial of kidney transplantation. Efficacy of tofacitinib as replacement of for tacrolimus in widely used immunosuppressive regimen (ATG, TNF α blocker, sirolimus, tacrolimus) in islet allo-transplantation setting was evaluated in cynomolgus monkeys (Macaca fascicularis) in this study.

Method

Five healthy male cynomolgus monkeys between 4 and 5 years old were used as recipients. Isolated aAllogeneic islets from cadaver or living donors (3,900~12,500 IEQ/kg) were infused via the portal vein. Immunosuppressive regimen consisted of ATG, humira, ± anakinra as for induction, and sirolimus, and tofacitinib as for maintenance therapy.

Result

Two monkeys were expired due to iatrogenic reasons around day 30 after transplantation (D30), though levels of monkey C-peptide were > 1.5 ng/ml without exogenous insulin. One monkey showed level of monkey C-peptide > 0.39 ng/ml until D54 while exogenous insulin being administered. Re-transplantation was performed at D90. Level of monkey C-peptide was detected at > 0.29 ng/ml until D131 with exogenous insulin administration. Another monkey revealed level of monkey C-peptide < 0.21 ng/ml at D41 with exogenous insulin administration. After re-transplantation at D70, level of monkey C-peptide was > 2.0 ng/ml until D365 with 80% of reduction of exogenous insulin requirement. Last monkey performed showed 84% of reduction of exogenous insulin requirement until D81 with level of monkey C-peptide > 1.3 ng/ml. After re-transplantation at D82, exogenous insulin treatment ceased until D210 with 3.5 ng/ml of level of monkey C-peptide.

Conclusion

Although we didn’t present results of the standard regimen group including tacrolimus group was not conducted in our this study for comparison in parallel, these our results showed demonstrated that tofacitinib could be a comparable maintenance immunosuppressive drug in islet allo-transplantation.

Conclusion

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 the National Research Foundation of Korea (Project No. 2016R1D1A1B03932507).

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