Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice

A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of antoimmune diabetes, This study was intended to find ways to prevent the development of NOD diab etes using a neutralizing anti-interleukin (IL)-12 antibody (C17.8) that in hibits Th1 cell differentiation, When C17.8 was administered from 5 to 30 w eeks of age, NOD mice exhibited suppression of both insulitis and diabetes. However, when C17.8 administration ceased at 15 weeks of age, 8 of 13 reci pients showed diabetes at 30 weeks of age. These results suggest that IL-12 plays an important role not only in the development of effector cells but also in their activation. In contrast, when C17.8 was injected into 2-week- old female NOD mice for 6 consecutive days, all 16 recipients showed diabet es at 30 weeks of age, whereas 12 of 20 control mice became diabetic. This result suggests that depletion of endogenous IL-12 at a young age results i n the enhancement of diabetes. Flow cytometric analysis indicated that acti vated memory T-cells were present in higher numbers after C17.8 treatment. Transfer of spleen cells from 15-meek-old C17.8-treated NOD mice to NOD-sci d mice resulted in an earlier onset and a higher incidence of diabetes. Fur thermore, administration of C17.8 to 2-meek-old NOD mice also resulted in a much earlier onset of diabetes. These results suggest that short-term trea tment with anti-IL-12 antibody prohibits IL-2 production at a young age, wh ich may influence the expansion and apoptosis of pathogenic T-cells, result ing in the acceleration of antoimmune diabetes.