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 on graft survival and evaluated its efficacy in immunomodulation of islet graft for transplantation. Male WS rats were used as islet donors and streptozotocin-induced diabetic C57BL/6 mice as recipients. The isolated islets were treated with MMC at concentrations of 0, 0.1, 1, 3.2, 10, 32, 100, 320, and 1000 microg/mL for 30 min, and were cultured for 20 h. Then, 300-400 islets were transplanted into the renal subcapsular 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 microg/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 days for culturing alone). Islets treated with MMC at a concentration of 320 microg/mL or more failed to restore normoglycemia in the diabetic recipient mice after transplantation. Viability of islets incubated with doses up to 100 microg/mL, assessed under the confocal microscope after propidium iodide and Hoechst 33342 staining, was maintained well comparable to that of freshly isolated islets, while those treated at 320 microg/mL was significantly decreased. Thus, a therapeutic window for MMC efficacy was found at concentrations from 10 microg/mL to 100 microg/mL. This modality is simple and effective and underlying molecular mechanisms need to be determined in the future.
Department of Surgery II, Osaka University Medical School, Yamadaoka, Suita, Japan.
T
T
Grochowiecki
M
M
Gotoh
K
K
Dono
Y
Y
Takeda
M
M
Nishihara
Y
Y
Ohta
F
F
Kimura
H
H
Ohzato
K
K
Umeshita
M
M
Sakon
M
M
Monden
D000818:Animals; D002469:Cell Separation; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D006085:Graft Survival; D007515:Islets of Langerhans / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000494:pharmacology*; D051381:Rats; D014183:Transplantation, Heterologous
D016685:Mitomycin