PRETREATMENT OF CRUDE PANCREATIC-ISLETS WITH MITOMYCIN-C (MMC) PROLONGS ISLET GRAFT-SURVIVAL IN A XENOGENEIC RAT-TO-MOUSE MODEL

In this study, we examined the effect of mitomycin C (MMC) treatment o n graft survival and evaluated its efficacy in immunomodulation of isl et graft for transplantation. Male WS rats were used as islet donors a nd streptozotocin-induced diabetic C57BL/6 mice as recipients. The iso lated islets were treated with MMC at concentrations of 0, 0.1, 1, 3.2 , 10, 32, 100, 320, and 1000 mu g/mL for 30 min, and were cultured for 20 h. Then, 300-400 islets were transplanted into the renal subcapsul ar space of diabetic mice. Significant prolongation of graft survival was obtained when the islets were treated with MMC at a concentration of 10, 32, or 100 mu g/mL (MST 23 +/- 7.4, 17.5 +/- 5.4, 29.6 +/- 9.7 days: p < 0.003,p < 0.012, p < 0.001, respectively, vs. 12.3 +/- 2.7 d ays for culturing alone). Islets treated with MMC at a concentration o f 320 mu g/mL or more failed to restore normoglycemia in the diabetic recipient mice after transplantation. Viability of islets incubated wi th doses up to 100 mu g/mL, assessed under the confocal microscope aft er propidium iodide and Hoechst 33342 staining, was maintained well co mparable to that of freshly isolated islets, while those treated at 32 0 mu g/mL was significantly decreased. Thus, a therapeutic window for MMC efficacy was found at concentrations from 10 mu g/mL to 100 mu g/m L. This modality is simple and effective and underlying molecular mech anisms need to be determined in the future. (C) 1998 Elsevier Science Inc.