PRIMARY NONFUNCTION OF ISLET GRAFTS IN AUTOIMMUNE DIABETIC NONOBESE DIABETIC MICE IS PREVENTED BY TREATMENT WITH INTERLEUKIN-4 AND INTERLEUKIN-10

In isologous islet transplantation in spontaneously diabetic nonobese diabetic (NOD) mice, destruction of the islet graft is caused by recur rence of T helper (Th)1-driven insulitis[fnc,1. We established a model of transplantation in which female NOD recipients were rendered diabe tic by a single injection of cyclophosphamide (250 mg/kg), Under these conditions, 500 freshly isolated islets from young NOD mice transplan ted under the kidney capsule did not lead to normoglycemia within 3 da ys after transplantation, but underwent immediate impairment of functi on, This primary nonfunction was seen in >80% of the recipients, Treat ment of the recipients with the Th2-associated cytokine interleukin (I L)-4 alone did not prevent primary nonfunction, whereas treatment of t he recipients with a combination of IL-4 and IL-10 restored immediate function of the grafts, Cytokine treatment did not prevent later rejec tion of grafts, Histological analysis of the grafts revealed less seve rely infiltrated islets, with well preserved islet architecture, in on ly normoglycemic animals treated with IL-4 or with IL-4 and IL-10, Sta ining for lymphocytes, macrophages, and tumor necrosis factor (TNF)-al pha did not show differences between the groups, but IFN-gamma was mar kedly less expressed in IL-4- and IL-10-treated grafts, Concomitantly, analysis of animals treated for 8 days after injection of cyclophosph amide, with IL-4 and IL-10, revealed a reduction of IL-12 mRNA in the pancreas. We conclude from these data that primary nonfunction of isle t grafts is prevented by treatment of the recipients with a combinatio n of IL-4 and IL-10, via downregulation of Th1 cytokines.