| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 99 === Heme oxygenase 1 (HO-1) has strong antiapoptotic, anti-inflammatory and antioxidative effects that help protect cells against various forms of immune attack. We investigated whether the transgenic expression of HO-1 in pancreatic cells would protect nonobese diabetic (NOD) mice from autoimmune damage and prolong graft survival following islet transplantation. We generated an insulin promoter-driven murine HO-1 (pINS-mHO-1) transgenic NOD mouse model to evaluate the protective effect of cell-specific HO-1 in autoimmune diabetes. Transgene expression, insulitis and the incidence of diabetes in mice were characterized. Lymphocyte composition, the development of Th1, Th2 and Treg cells, T cell proliferation and lymphocyte-mediated disease transfer were analyzed. The potential effects of transgenic islets and islet transplantation on apoptosis, inflammation and the generation of reactive oxygen species (ROS) were evaluated. Transgenic mice showed less severe insulitis and a lower incidence of diabetes than nontransgenic control littermates. Lymphocyte compositions and functions were not affected. Islets from transgenic mice expressed lower levels of proinflammatory cytokines/chemokines, proapoptotic gene expression and amounts of ROS, and were more resistant to TNF- and IFN--induced apoptosis. Moreover, islet grafts from transgenic mice survived longer in diabetic recipients than control islets. Transgenic overexpression of HO-1 in cells protected NOD mice from diabetes and delayed the autoimmune destruction of islet grafts, providing valuable insight toward the development of better strategies for clinical islet transplantation in patients with type 1 diabetes.
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