XIAP overexpression in islet β-cells enhances engraftment and minimizes hypoxia-reperfusion injury

Abstract

Recent advances in clinical islet transplantation have allowed patients with type 1 diabetes to become insulin independent, but the procedure is limited since islets from two donors per recipient are typically required. This limitation arises because within a few days of the islets being embolized into the portal circulation, at least half of the transplanted β-cells have undergone apoptotic cell death triggered by hypoxic and chemokine/cytokine- mediated stress. We hypothesized that the survival of β-cells in the early post-transplant period would be enhanced if naturally occurring inhibitor of apoptosis proteins (IAPs) were transiently overexpressed in the grafts. In the present study, we used a growth-regulatable β-cell line (βTC-Tet) as a model for β-cells within islets, and examined whether adenovirally delivered XIAP (X-linked IAP-a highly potent IAP) could enhance β-cell survival. In vitro, XIAP-expressing βTC-Tet cells were markedly resistant to apoptosis in an ischemia-reperfusion injury model system and following exposure to cytokines. When Ad-XIAP transduced βTC-Tet cells were transplanted subcutaneously into immunodeficient mice, the grafts were able to reverse diabetes in 3 days, vs. 21 days for Ad-βGal transduced cells. This approach may allow more efficient use of the limited existing supply of human islets. Copyright © Blackwell Munksgaard 2005.