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

Abstract

Allotransplantation of pancreatic islets represents a promising approach to treat type 1 diabetes. Destruction of ␤-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 ␤-cells from apoptosis, we used a recombinant adenovirus to overexpress XIAP in transformed murine ␤-cells and in freshly isolated islets. In vitro cytokine-induced ␤-cell death was decreased to baseline levels in XIAPtransduced 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 ϳ17 days posttransplantation due to graft rejection. Immunohistochemistry revealed preservation of ␤-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. Diabetes 54:2533-2540, 2005

XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model

“…11 In the present study we asked whether XIAP overexpression could increase the cure rate of suboptimal, syngeneic islets grafts and decrease the number of days required to Figure 1. establishment of a suboptimal, syngeneic islet transplantation model in streptozotocin-induced diabetic recipients.…”

“…11 By engrafting more robust islets that are less prone to undergoing apoptosis, the likelihood of alerting the Figure 2. Restoration of euglycemia in streptozotocin-induced diabetic recipients of a suboptimal islet graft.…”

“…We have previously reported efficient reporter gene expression following transduction with 5 pfu Ad-LacZ as well as demonstrated substantial XIAP protein expression following transduction with 5 pfu Ad-XIAP as assessed by western blot analysis. 11 We found that a suboptimal graft of 100 XIAP-transduced islets restored euglycemia in 86% (12 of 14) of the recipients within 8.4 ± 2.0 days (Table 1, Fig. 2A).…”

“…10 New approaches that decrease the number of islets needed for successful transplantation or enhance graft function in the immediate post-transplant period could have a major impact on the long-term success of islet transplants and XIap inhibition of b-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model annette plesner, 1, * Galina soukhatcheva, 1 Robert G. Korneluk 2 and c. Bruce Verchere the number of diabetic recipients that could benefit from the procedure. We and others have previously shown the beneficial effects of islet overexpression of the X-linked inhibitor of apoptosis, XIAP, in protecting islet b-cells from death induced by cytokines, 11 TNFrelated apoptosis-inducing ligand, 12 hypoxia 13 and immunosuppressive drugs.…”

“…14 Furthermore, XIAP has been shown to protect murine islets following allo-transplantation into diabetic recipients 11 as well as human islets transplanted into immune-deficient diabetic mice. 15 XIAP is a potent inhibitor of cell death induced by a number of apoptotic triggers, presumably through its ability to inhibit caspases 3, 7 and 9.…”