TNF-ALPHA DOWN-REGULATES TYPE-1 CYTOKINES AND PROLONGS SURVIVAL OF SYNGENEIC ISLET GRAFTS IN NONOBESE DIABETIC MICE

Administration of TNF-alpha to autoimmune diabetes-prone nonobese diab etic mice and biobreeding rats inhibits diabetes development; however, the mechanism(s) of diabetes prevention by TNF-alpha has not been est ablished. We used the model of syngeneic islet transplantation into di abetic nonobese diabetic mice to study the effects of TNF-alpha admini stration on the types of mononuclear cells and cytokines expressed in the islet grafts and on autoimmune diabetes recurrence. Twice daily i. p. injections of TNF-alpha (20 mu g/day) from day 1 to day 30 after is let transplantation significantly prolonged islet graft survival; thus , 70% (16 of 23) of mice treated with TNF-alpha were normoglycemic at 30 days after islet transplantation compared with none (0 of 14) of ve hicle-treated control mice. Islet grafts and spleens from TNF-alpha-tr eated mice at 10 days after islet transplantation contained significan tly fewer CD4(+) and CD8(+) T cells, and significantly decreased mRNA levels of type 1 cytokines (IFN-gamma, IL-2, and TNF-beta) than islet grafts and spleens from control mice. Regarding type 2 cytokines, IL-4 mRNA levels were not changed significantly in islet grafts or spleens of TNF-alpha-treated mice, whereas IL-10 mRNA levels were decreased s ignificantly in islet grafts of TNF-alpha-treated mice and not signifi cantly changed in spleens. TGF-beta mRNA levels in islet grafts and sp leens were similar in TNF-alpha-treated and control mice. These result s suggest that TNF-alpha partially protects beta cells in syngeneic is let grafts from recurrent autoimmune destruction by reducing CD4(+) an d CD8(+) T cells and down-regulating type 1 cytokines, both systemical ly and locally in the islet graft.