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.

胰岛移植可有效预防所选的1型糖尿病患者的严重低血糖症和血糖负担。但是，由于钙调神经磷酸酶抑制剂（CNI）会引起β细胞和肾毒性，因此非常需要具有与CNI相似的效力和安全性的替代药物。在这里，我们测试了猕猴非人灵长类动物（NHP）模型中CIT07免疫抑制方案中是否可以使用JAK3抑制剂托法替尼代替他克莫司。将五只独立的链脲佐菌素（STZ）诱导的糖尿病猴子移植了MHC不匹配的异基因胰岛，并将三只动物在血糖控制不充分或早期胰岛移植排斥后再次移植。胰岛移植后 血糖水平迅速稳定，通过血清C肽浓度测量的最大胰岛移植物存活时间在移植后（中位生存日； 98天）分别为> 330、98，> 134、31或22天。在随访期间，基于JAK3抑制剂的免疫抑制可有效抑制细胞和体液免疫应答。尽管通过定量实时PCR分析检测到食蟹猕猴巨细胞病毒（CMV）的基因组拷贝数间歇性增加，但并未在所有动物中发现严重感染或移植后淋巴增生性疾病（PTLD）。在一起