Permanent acceptance of mitomycin C-treated islet allograft.

Background. Mitomycin C (MMC) treatment produces genotoxic stress and exerts various biologic effects on cell function. This study determines the feasibility of MMC pretreatment of islet grafts as a sole immunomodulatory regimen to protect murine crude-digested islet allografts. Methods. Collagenase-digested BALB/c (H-2 d ) islets were incubated for 30 min with MMC at different doses (0, 3.2, 10, 32, and 100 μg/mL; n=20, 15, 55, 15, 15, respectively), cultured for 20 hr, and transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 (B6; H-2 b ) mice. Results. All mice that received MMC-treated islets showed restoration of normoglycemia within 5 days postgrafting, which was maintained until rejection. All untreated islets were acutely rejected with a mean survival time of 15.1±3.5 days. Significant prolongation of graft survival was noted in mice undergoing transplantation with islets treated with 10 μg/mL MMC compared with untreated islets (58.9±37.7 days, P<0.01). Notably, the grafts of 24 of 55 animals (43%) that received islets treated with 10 μg/mL MMC survived more than 100 days without any other treatment. Furthermore, antigen-specific prolongation of graft survival of secondary untreated islets was observed in mice bearing long-term functioning islet grafts. Conclusions. Our results indicate that pretreatment of islets with MMC alone protects the graft against rejection and produces long-term graft survival with normal blood glucose levels, and that pretreatment with MMC offers a new strategy for allogeneic islet transplantation.