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XIAP Overexpression in Human Islets Prevents Early Posttransplant Apoptosis and Reduces the Islet Mass Needed to Treat Diabetes

¹ Alberta Diabetes Institute (ADI), University of Alberta, Edmonton, Alberta, Canada
² Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
³ Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
⁴ Solange-Gauthier-Karsh Molecular Genetics Laboratory, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Canada
⁵ Clinical Islet Program, University of Alberta, Edmonton, Alberta, Canada

The Edmonton Protocol for treatment of type 1 diabetes requires islets from two or more donors to achieve euglycemia in a single recipient, primarily because soon after portal infusion, the majority of the transplanted cells undergo apoptosis due to hypoxia and hypoxia reperfusion injury. X-linked inhibitor of apoptosis protein (XIAP) is a potent endogenous inhibitor of apoptosis that is capable of blocking the activation of multiple downstream caspases, and XIAP overexpression has previously been shown to enhance engraftment of a murine ß-cell line. In this study, human islets transduced with a XIAP-expressing recombinant adenovirus were resistant to apoptosis and functionally recovered following in vitro stresses of hypoxia and hypoxia with reoxygenation (models reperfusion injury). Furthermore Ad-XIAP transduction dramatically reduced the number of human islets required to reverse hyperglycemia in chemically diabetic immunodeficient mice. These results suggest that by transiently overexpressing XIAP in the immediate posttransplant period, human islets from a single donor might be used to effectively treat two diabetic recipients.

Key Words: GAL, galactosidase • Hu-XIAP, human XIAP • TUNEL, TdT-mediated dUTP nick-end labeling • XIAP, X-linked inhibitor of apoptosis protein

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