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 diabetic mice and biobreeding rats inhibits diabetes development; however, the mechanism(s) of diabetes prevention by TNF-alpha has not been established. We used the model of syngeneic islet transplantation into diabetic nonobese diabetic mice to study the effects of TNF-alpha administration 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 microg/day) from day 1 to day 30 after islet 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 vehicle-treated control mice. Islet grafts and spleens from TNF-alpha-treated mice at 10 days after islet transplantation contained significantly 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 significantly in islet grafts of TNF-alpha-treated mice and not significantly changed in spleens. TGF-beta mRNA levels in islet grafts and spleens were similar in TNF-alpha-treated and control mice. These results suggest that TNF-alpha partially protects beta cells in syngeneic islet grafts from recurrent autoimmune destruction by reducing CD4+ and CD8+ T cells and down-regulating type 1 cytokines, both systemically and locally in the islet graft.
Rabinovitch
A
A
Department of Medicine, University of Alberta, Edmonton, Canada.
Suarez-Pinzon
W L
WL
Sorensen
O
O
Rajotte
R V
RV
Power
R F
RF
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods; D006085:Graft Survival / Q000187:drug effects* / Q000235:genetics; D016130:Immunophenotyping; D007515:Islets of Langerhans / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB; D013154:Spleen / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha