Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes

Nonobese diabetic (NOD) mice develop spontaneous insulin-dependent diabetes mellitus (IDDM), and the pancreas-infiltrating T cells invariably show a Th1 phenotype. We demonstrated here that the interleukin (IL)-12 antagonist (p40)(2) can deviate the default Th1 development of naive T cell receptor (TCR)-transgenic CD4(+) cells to the Th2 pathway in vitro. Although (p40)(2) does not modify the cytokine profile of polarized Th1 cells, it prevents further recruitment of CD4(+) cells into the Th1 subset. To study the involvement of Th1 and Th2 cells in the initiation and progression of IDBM, we targeted endogenous IL-12 by administration of (p40)(2) in NOD mice. (p40)(2) administration to NOD mice inhibits interferon-gamma but not IL-10 production in response to lipopolysaccharide (LPS) or to the putative autoantigen IA-2. Serum immunoglobulin isotypes determined after (p40)(2) treatment indicate an increase in Th2 and a decrease in Th1 helper activity. Administration of (p40)(2) from 3 weeks of age onwards, before the onset of insulitis, results in the deviation of pancreas-infiltrating CD4(+) but not CD8(+) cells to the Th2 phenotype as well as in the reduction of spontaneous and cyclophosphamide-accelerated IDDM. After treating NOD mice with (p40)(2) from 9 weeks of age, when insulitis is well established, few Th2 and a reduced percentage of Th1 cells are found in the pancreas. This is associated with a slightly decreased incidence of spontaneous IDDM, but no protection from cyclophosphamide-accelerated IDDM. In conclusion, deviation of pancreas-infiltrating CD4(+) cells to Th2 is associated with protection from IDDM. However, targeting IL-12 after the onset of insulitis, when the pancreas contains polarized Th1 cells, is not sufficient to induce an effective immune deviation able to significantly modify the course of disease.