Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1

Interferon regulatory factor-1 IRF-1), a transcriptional factor, regulates type I interferon and interferon-induced genes. It was reported that IRF-1 regulates important molecules required for inflammation and immune reaction s. To investigate the role of IRF-1 in the development of autoimmune diabet es, we established IRF-1 deficient (IRF-1(-/-)) non-obese diabetic (NOD) mi ce. TRF-1-deficient C57BL/6J mice were out-crossed to NOD mice, and F1 were backcrossed to NOD mice. At the N8 generation, the heterozygote for IRF-1 mutation was intercrossed and N8F1 was obtained. Out of three NOD genotypes , IRF-1(+/+) and IRF-1(+/-) developed spontaneous diabetes with an incidenc e of 47% (9/19) and 50% (10/20) by 30 weeks of age, respectively; whereas I RF-1(-/-) did not develop diabetes (0/18, P <0.01 vs. (+/+) and (+/-)). His tologically, IRF-1(+/+) and IRF-1(+/-) had various degrees of insulitis, bu t IRF-1(-/-) had no insulitis. In comparison with IRF-1(+/+), the percentag e of CD4(+) and Mac-1(+) splenic cells significantly increased, whereas CD3 (+), CD8(+) and B220(+) cells decreased in IRF-1(-/-). Furthermore, spleen cell proliferation in response to Con A or murine GAD65 peptide, a major au toantigen of the pancreatic P-cell, significantly increased, and the IFN-ga mma /IL-10 ratio in the culture supernatant significantly decreased in IRF- 1(-/-), suggesting Th2 deviation in cytokine balance. These results indicat e that IRF-1 plays a key role in developing insulitis and diabetes in NOD m ice. (C) 2001 Academic Press.