Caspase inhibitor therapy enhances marginal mass islet graft survival and preserves long-term function in islet transplantation

Islet transplantation can provide insulin independence in patients with type 1 diabetes, but islets derived from two or more donors are often required. A significant fraction of the functional islet mass is lost to apoptosis in the immediate posttransplant period. The caspase inhibitor N-benzyloxycabonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD-FMK) has been used therapeutically to prevent apoptosis in experimental animal models of ischemic injury, autoimmunity, and degenerative disease. In the current study, zVAD-FMK therapy was examined in a syngeneic islet transplant model to determine whether caspase inhibition could improve survival of transplanted islets. zVAD-FMK therapy significantly improved marginal islet mass function in renal subcapsular transplantation, where 90% of zVAD-FMK-treated mice became euglycemic with 250 islets, versus 27% of the control animals (P < 0.001). The benefit of zVAD-FMK therapy was further demonstrated after intraportal transplantation, where 75% of zVAD-FMK-treated animals established euglycemia with only 500 islets, and all of the controls remained severely diabetic (P < 0.001). zVAD-FMK pretreatment of isolated islets in the absence of systemic therapy resulted in no significant benefit compared with controls. Long-term follow-up of transplanted animals beyond 1 year posttransplant using glucose tolerance tests confirmed that a short course of zVAD-FMK therapy could prevent metabolic dysfunction of islet grafts over time. In addition, short-term zVAD-FMK treatment significantly reduced posttransplant apoptosis in islet grafts and resulted in preservation of graft insulin reserve over time. Our data suggest that caspase inhibitor therapy will reduce the islet mass required in clinical islet transplantation, perhaps to a level that would routinely allow for insulin independence after single-donor infusion.