TREATMENT WITH NEUTRALIZING ANTIBODIES SPECIFIC FOR IL-1-BETA PREVENTS CYCLOPHOSPHAMIDE-INDUCED DIABETES IN NONOBESE DIABETIC MICE

Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of IDDM, but it is not clear which form, IL-1 alpha or IL-1 beta, is predominantly implicated. In this study, we have evaluated the contrib ution of IL-1 beta by treating diabetes-prone nonobese diabetic (NOD) mice with specific neutralizing antibodies. First, we assessed the neu tralizing potential of these antibodies in C57BL/6 mice under acute se ptic shock by measuring IL-1 beta in sera 4 h after lipopolysaccharide injection. One milligram and 0.1 mg of anti-IL-1 beta antibodies (Abs ) were capable of neutralizing the IL-1 beta produced, and the effect persisted for at least 5 days. Second, we evaluated the role of IL-1 b eta in the cyclophosphamide (CY)-accelerated model of diabetes. Nondia betic male NOD mice were injected with 200 mg/kg CY and treated twice weekly with anti-IL-1 beta Ab. The incidence of diabetes reached 76 an d 100% in the control groups treated with 0.25 and 0.1 mg rabbit IgG, respectively. In contrast, only 34% of mice treated with 0.25 mg of an ti-IL-1 beta Ab became diabetic. In the group treated with 0.1 mg of a nti-IL-1 beta Ab, 89% of the mice became diabetic in the same period o f time, demonstrating that the protective effect was dose dependent. O ur results show that IL-1 beta is a critical effector molecule in this model of IDDM and that its specific inhibition could be an attractive target for therapeutic intervention.