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IL-12 Administration Accelerates Autoimmune Diabetes in Both Wild-Type and IFN--Deficient Nonobese Diabetic Mice, Revealing Pathogenic and Protective Effects of IL-12-Induced IFN-¹

BioXell, Milan, Italy

IL-12 administration to nonobese diabetic (NOD) mice induces IFN--secreting type 1 T cells and high circulating IFN- levels and accelerates insulin-dependent diabetes mellitus (IDDM). Here we show that IL-12-induced IFN- production is dispensable for diabetes acceleration, because exogenous IL-12 could enhance IDDM development in IFN--deficient as well as in IFN--sufficient NOD mice. Both in IFN-^+/- and IFN-^-/- NOD mice, IL-12 administration generates a massive and destructive insulitis characterized by T cells, macrophages, and CD11c⁺ dendritic cells, and increases the number of pancreatic CD4⁺ cells secreting IL-2 and TNF-. Surprisingly, IL-12-induced IFN- hinders pancreatic B cell infiltration and inhibits the capacity of APCs to activate T cells. Although pancreatic CD4⁺ T cells from IL-12-treated IFN-^-/- mice fail to up-regulate the P-selectin ligand, suggesting that their entry into the pancreas may be impaired, T cell expansion is favored in these mice compared with IL-12-treated IFN-^+/- mice because IL-12 administration in the absence of IFN- leads to enhanced cell proliferation and reduced T cell apoptosis. NO, an effector molecule in cell destruction, is produced ex vivo in high quantity by pancreas-infiltrating cells through a mechanism involving IL-12-induced IFN-. Conversely, in IL-12-treated IFN--deficient mice, other pathways of cell death appear to be increased, as indicated by the up-regulated expression of Fas ligand on Th1 cells in the absence of IFN-. These data demonstrate that IFN- has a dual role, pathogenic and protective, in IDDM development, and its deletion allows IL-12 to establish alternative pathways leading to diabetes acceleration.

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