COMBINED THERAPY WITH INTERLEUKIN-4 AND INTERLEUKIN-10 INHIBITS AUTOIMMUNE DIABETES RECURRENCE IN SYNGENEIC ISLET-TRANSPLANTED NONOBESE DIABETIC MICE ANALYSIS OF CYTOKINE MRNA EXPRESSION IN THE GRAFT


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Abstract

Syngeneic pancreatic islet grafts in nonobese diabetic (NOD) mice elicit a cell-mediated autoimmune response that destroys the insulin-producing β cells in the islet graft. IL-4 and IL-10 are cytokines that inhibit cell-mediated immunity. In this study, we evaluated the effects of IL-4 and IL-10 on the survival of syngeneic pancreatic islets transplanted into diabetic NOD mice. Islet grafts survived beyond 18 days and normoglycemia was maintained in 67% (10 of 15) of mice treated with IL-4 plus IL-10, but in none (0 of 20) of vehicle-injected (control) mice. Also, 40% (6 of 15) of the mice treated with IL-4 plus IL-10 were normogly-cemic at 30 days after transplantation, compared with 14% (1 of 7) of the mice treated with IL-4 alone, 8% (1 of 13) of the mice treated with IL-10 alone, and none (0 of 20) of the control mice. Histological examination of grafts at 10 days after transplantation revealed periislet accumulations of mononuclear leukocytes and intact islet β cells in grafts from IL-4 plus IL-10 treated mice, whereas islets were infiltrated by leukocytes and the β cell mass was greatly reduced in grafts from control mice. Polymerase chain reaction (PCR) analysis of cytokine mRNA expression in the grafts revealed higher levels of IL-2, IFNγ and IL-10 mRNA in grafts of diabetic compared with normoglycemic control mice, whereas D7Nγ and TNFα mRNA levels were significantly decreased in grafts of IL-4 plus IL-10-treated mice compared with either normoglycemic or diabetic control mice. These results suggest that T helper (Th)1 cells and their cytokine products (IL-2, IFNγ and TNFα) may promote islet β cell destructive insulitis and autoimmune diabetes recurrence in syngeneic islet-transplanted NOD mice, and that administration of IL-4 plus IL-10 may inhibit diabetes recurrence by suppressing Th1 cytokine production in the islet grafts.

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