SUPPRESSION OF CYCLOPHOSPHAMIDE-INDUCED DIABETES DEVELOPMENT AND PANCREATIC TH1 REACTIVITY IN NOD MICE TREATED WITH THE INTERLEUKIN (IL)-12ANTAGONIST IL-12(P40)(2)

The macrophage product interleukin (IL)-12 is known to drive Th1 react ions in physiological and pathological immune responses. Here we repor t that treatment with the homodimeric IL-12p40 subunit, an antagonist of the bioactive IL-12p35/p40 heterodimer, suppresses diabetes develop ment in cyclophosphamide-injected NOD mice. Female mice of 70 days old received cyclophosphamide (250 mg/kg) to accelerate and synchronize d iabetes development, and daily injections of 1 mu g IL-12(p40)(2). Whi le there was no delay of the first diabetes cases, the incidence of ov ert diabetes was significantly decreased in treated mice (46 vs 23 %,p < 0.05). Analysis of mRNA expression in the pancreas showed that admi nistration of the IL-12 antagonist had dampened interferon-gamma gene expression, decreased the ratio of interferon-gamma/IL-10 mRNA levels and in parallel suppressed the expression of the inducible nitric oxid e synthase. At the same time intra-islet infiltration was significantl y decreased (p < 0.001). Interestingly, the administration of IL-12(p4 0)(2) also affected IL-12 gene expression, by downregulation of p35 mR NA. We conclude that IL-12 p40 homodimer suppresses diabetes developme nt in the NOD mouse by dampening islet inflammation via selective down regulation of Th1 type responses. The naturally occurring IL-12 antago nist IL-12(p40)(2) represents a new and specific Th1 directed approach to prevent autoimmune diabetes.