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

Autor: Jongwon Ha, Jiyeon Kim, Byoung Hoon Min, Seong Jun Kang, Il Hee Yoon, Chung Gyu Park, Eung Soo Hwang, Jun Seop Shin, Jong Min Kim, Hyunwoo Chung
Rok vydání: 2019
Předmět:
Graft Rejection
Male
0301 basic medicine
Transplantation Conditioning
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Transplantation
Heterologous
Drug Evaluation
Preclinical
Islets of Langerhans Transplantation
030209 endocrinology & metabolism
Pharmacology
Article
Diabetes Mellitus
Experimental
03 medical and health sciences
0302 clinical medicine
Endocrinology
Transplantation Immunology
medicine
Animals
Protein Kinase Inhibitors
Immunosuppression Therapy
Type 1 diabetes
geography
geography.geographical_feature_category
Tofacitinib
business.industry
Graft Survival
Janus Kinase 3
Immunosuppression
medicine.disease
Streptozotocin
Islet
Tacrolimus
Calcineurin
Transplantation
Macaca fascicularis
surgical procedures
operative
030104 developmental biology
Female
business
Immunosuppressive Agents
medicine.drug
Zdroj: Islets
ISSN: 1938-2022
1938-2014
Popis: 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.
Databáze: OpenAIRE
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