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The X-Linked Inhibitor of Apoptosis Protein Enhances Survival of Murine Islet Allografts

¹ Department of Pathology and Laboratory Medicine, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada
² Department of Pediatrics, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada

Allotransplantation of pancreatic islets represents a promising approach to treat type 1 diabetes. Destruction of ß-cells in islet allografts involves multiple immune mechanisms that lead to activation of caspases and apoptotic cell death. The X-linked inhibitor of apoptosis (XIAP) inhibits apoptosis induced by a variety of triggers, primarily by preventing the activation of caspases. To determine whether XIAP would protect ß-cells from apoptosis, we used a recombinant adenovirus to overexpress XIAP in transformed murine ß-cells and in freshly isolated islets. In vitro cytokine-induced ß-cell death was decreased to baseline levels in XIAP-transduced MIN-6 and NIT-1 cell lines compared with controls. To evaluate the potential of XIAP overexpression to prevent in vivo allogeneic graft rejection, we transduced Balb/c islets ex vivo with XIAP before transplantation into CBA mice with streptozotocin-induced diabetes. We observed that almost all mice receiving allografts of XIAP-expressing islets maintained normoglycemia until the experiment was terminated (45–72 days posttransplant), whereas control mice receiving islets transduced with adenovirus expressing LacZ were hyperglycemic by 17 days posttransplantation due to graft rejection. Immunohistochemistry revealed preservation of ß-cells and clearance of infiltrating immune cells in the XIAP-expressing islet grafts. The in vitro allogeneic response of splenocytes isolated from recipients of XIAP-expressing grafts 8 weeks posttransplant was similar to that seen in nonprimed allogeneic mice, suggesting that XIAP overexpression may lead to the acceptance of islet allografts in diabetic recipients. Long-term protection of islet allografts by XIAP overexpression may enhance the survival of islet transplants in diabetes.

Abbreviations: IFN, interferon; IL, interleukin; MOI, multiplicity of infection; TNF, tumor necrosis factor; XIAP, X-linked inhibitor of apoptosis

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