Overexpression of suppressor of cytokine signaling 1 in islet grafts results in anti-apoptotic effects and prolongs graft survival

Aims: A significant portion of islet grafts are destroyed by apoptosis and fail to become functional after transplantation. Strategies that enhance islet resistance to apoptosis may prevent graft loss. The aim of this study was to investigate whether overexpression of suppressor of cytokine signaling 1 (SOCS1) in islet grafts could achieve an anti-apoptotic effect and prolong graft survival. Main methods: We used a chimeric adenovirus vector (Ad5F35) to enhance SOCS1 expression in isolated rat islets, and assessed its protective action against TNF-alpha-induced apoptosis. After transplanting SOCS1-overexpressing islets into allogeneic recipients with streptozotocin-induced diabetes, graft survival and in situ apoptosis were analyzed using immunohistochemistry. Key findings: The isolated rat islets infected with Ad5F35-SOCS1 showed significantly higher SOCS1 expression than Ad5F35-EGFP and mock infected islets. The Ad5F35 transfection and SOCS1 overexpression on islets did not affect their insulin secretory function. After treatment with rat TNF-alpha and cycloheximide in vitro, Ad5F35-SOCS1 infected islets exhibited a lower apoptotic ratio than controls (Ad5F35-EGFP and mock infected islets). The diabetic recipients transplanted with Ad5F35-SOCS1 infected islets displayed longer time of normoglycemia than recipients transplanted with mock infected islets. Furthermore, histological analysis indicated that the infected grafts with local overexpression of SOCS1 showed decreased apoptosis in the early post-transplant period. Significance: These results demonstrate that overexpression of SOCS1 in islet grafts prior to transplantation can significantly protect them from apoptotic loss and prolong their survival. This approach might find a clinical counterpart. (C) 2009 Elsevier Inc. All rights reserved.