Date: Saturday, April 29, 2017
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall D1
Janus kinase 3 (JAK3) is one of the molecules that make up the JAK-STAT signaling pathway that regulates numerous 40 cytokines. Thus, this cascade can be an attractive therapeutic target for immunosuppression. In fact, FDA-approved JAK3 inhibitor, tofacitinib, is used clinically to treat RA. The aim of this study was to investigate the applicability of tofacitinib to prevent graft rejection in islet transplantation and to elucidate the detailed mechanisms that enable long-term graft survival.
First, the immunosuppressive effect of tofacitinib was examined in pig-to-mouse islet xenoTx. Porcine islets (5000 IEQs) were transplanted at the renal subcapsular site of diabetic B6 mice. The recipients were divided into 3 groups including control group (n=5, no treatment), tofacitinib group (n=7, 15 mg/kg, BID, PO) and tacrolimus group (n=5, 1mg/kg). The graft survival was significantly prolongled and normoglycemia was maintained in tofacitinib group in comparison to the untreated control group and tacrolimus group.
Next, to determine the mechanisms of the superior effect of tofacitinib over tacrolimus in maintaining normoglycemia, we investigated β cell-protective effect of tofacitinib. The MIN6 β cell line was treated with H2O2 in the presence and absence tofacitinib.The viability of MIN6 cells was increased dose-dependently following tofacitinib treatment. We also performed murine syngeneic islet Tx of marginal mass of islets (200 IEQs) at renal subcapsular site to assess the mass-sparing effect of tofacitinib in vivo. In the untreated group, only 50% of the mice maintained normoglycemia, while 100% of mice maintained normoglycemia in the tofacitinib-treated group. This suggests that tofacitinib could protect pancreatic islets from ROS damage that occurs in the early periods of Tx.
Using these models, we have shown that tofacitinib could be an islet-friendly immunosuppressive agent and be more effective than other immunosuppressants that we have used in islet transplantation.
CITATION INFORMATION: Kang S.-J, Chung H, Lee S, Shin J.-S, Kim H.-J, Kim J.-M, Min B.-H, Choi S, Park C.-G. The Beneficial Effect of Janus Kinase 3 Inhibitor on Transplanted Islet via Protection from Oxidative Stress-Induced β Cell Death. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Kang S-J, Chung 4H, Lee 4S, Shin 4J-S, Kim H-J, Kim 4J-M, Min B-H, Choi S, Park1 4C-G. The Beneficial Effect of Janus Kinase 3 Inhibitor on Transplanted Islet via Protection from Oxidative Stress-Induced β Cell Death. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/the-beneficial-effect-of-janus-kinase-3-inhibitor-on-transplanted-islet-via-protection-from-oxidative-stress-induced-cell-death/. Accessed September 29, 2020.
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