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

Syngeneic pancreatic islet grafts in nonobese diabetic (NOD) mice elic it a cell-mediated autoimmune response that destroys the insulin-produ cing beta cells in the islet graft, IL-4 and IL-10 are cytokines that inhibit cell-mediated immunity, In this study, we evaluated the effect s of IL-4 and IL-10 on the survival of syngeneic pancreatic islets tra nsplanted into diabetic NOD mice, Islet grafts survived beyond 18 days and normoglycemia was maintained in 67% (10 of 15) of mice treated wi th 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 w ere normoglycemic 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. His tological examination of grafts at 10 days after transplantation revea led peri-islet accumulations of mononuclear leukocytes and intact isle t beta cells in grafts from IL-4 plus IL-10-treated mice, whereas isle ts were infiltrated by leukocytes and the beta cell mass was greatly r educed in grafts from control mice. Polymerase chain reaction (PCR) an alysis of cytokine mRNA expression in the grafts revealed higher level s of IL-2, IFN gamma, and IL-10 mRNA in grafts of diabetic compared wi th normoglycemic control mice, whereas IFN gamma and TNF alpha mRNA le vels were significantly decreased in grafts of IL-4 plus IL-10-treated mice compared with either normoglycemic or diabetic control mice. The se results suggest that T helper (Th)1 cells and their cytokine produc ts (IL-2, IFN gamma, and TNF alpha) may promote islet beta cell destru ctive 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.