IL-12 plays a pathologic role at the inflammatory loci in the development of diabetes in NOD mice

Accumulating evidence suggests that CD4(+) T helper type 1 (Th1) cells play a major role in the development of insulin-dependent diabetes mellitus (ID DM) in the non-obese diabetic (NOD) mouse model. Interleukin (IL)-12 is a p otent immunoregulatory molecule that is a key determinant of T-cell differe ntiation into Th1 cells, and has been implicated in the development of IDDM . To investigate the role of IL-12 that is locally produced by islet-infilt rating cells in the development of IDDM, we generated transgenic NOD mice i n which the IL-12 p40 homodimer, a natural antagonist of IL-12, was produce d exclusively in islets without affecting the levels of IL-12 p40 in the sy stemic circulation. We found that the incidence of diabetes was significant ly reduced in these transgenic mice. These results clearly demonstrate that IL-12 locally produced by islet-infiltrating cells plays a critical role i n the development of IDDM. (C) 2001 Academic Press.