Survival of mitomycin C-treated pancreatic islet xenografts is mediated by increased expression of transforming growth factor-??1

Background. Mitomycin C (MMC) can trigger various intracellular signals. The authors previously showed that pretreatment of highly immunogenic crude pancreatic islets with MMC improved their survival in a rat-to-mouse transplantation model. The aim of this study was to investigate the role of transforming growth factor (TGF)-β in mediating MMC-induced survival of islet xenografts. Methods. Collagenase-digested islets obtained from WS rats (RT1k) were incubated for 30 min with 10 μg/mL MMC and then transplanted into streptozotocin-induced diabetic C57BL/6 (H-2b) mice after 20 hr of culture at 37°C. Results. Survival of xenografts was enhanced by pretreatment of islets with MMC. MMC-treated xenografts showed a mild inflammatory cell response and significantly minimal infiltration of macrophages, CD4 + T cells, and CD8 + T cells compared with untreated grafts. TGF-β mRNA was increased at 20 hr after MMC treatment, and TGF-β protein expression was also increased compared with untreated islet xenografts. TGF-β concentration in blebs formed around the xenografts (but not in the serum) was higher in animals that underwent transplantation with MMC-treated islets than with untreated islets. Simultaneous transplantation of MMC-treated and untreated islets separately in each kidney of recipient mice showed that protection was only found in MMC-treated islets. Treatment of islets before transplantation by neutralizing anti-TGF-β antibody suppressed the MMC-protective effects on graft survival, whereas no such effect was noted with isotype-matched immunoglobulin. Conclusions. The authors' results indicate that MMC treatment effectively reduces local inflammatory response and that such effects are mediated by increase of TGF-β during the early period of islet transplantation.