Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice

IL-12 and IL-12 antagonist administration to nonobese diabetic (NOD) mice a ccelerates and prevents insulin-dependent diabetes mellitus (IDDM), respect ively, To further define the role of endogenous IL-12 in the development of diabetogenic Th1 cells, IL-12-deficient NOD mice were generated and analyz ed. Th1 responses to exogenous Ags were reduced by similar to 80% in draini ng lymph nodes of these mice, and addition of IL-12, but not IL-18, restore d Th1 development in vitro, indicating a nonredundant role of IL-12, Moreov er, spontaneous Th1 responses to a self Ag, the tyrosine phosphatase-like I A-2, were undetectable in lymphoid organs from IL-12-deficient, in contrast to wild-type, NOD mice. Nevertheless, wild-type and IL-12-deficient NOD mi ce developed similar insulitis and IDDM, Both in wild-type and IL-12-defici ent NOD mice, similar to 20% of pancreas-infiltrating CD4(+) T cells produc ed IFN-gamma, whereas very few produced IL-10 or IL-4, indicating that IDDM was associated with a type 1 T cell infiltrate in the target organ. T cell recruitment in the pancreas seemed favored in IL-12-deficient NOD mice, as revealed by increased P-selectin ligand expression on pancreas-infiltratin g T cells, and this could, at least in part, compensate for the defective T h1 cell pool recruitable from peripheral lymphoid organs. Residual Th1 cell s could also accumulate in the pancreas of IL-12-deficient NOD mice because Th2 cells were not induced, in contrast to wild-type NOD mice treated with an IL-12 antagonist. Thus, a regulatory pathway seems necessary to counter act the pathogenic Th1 cells that develop in the absence of IL-12 in a spon taneous chronic progressive autoimmune disease under polygenic control, suc h as IDDM.