Prevention of lupus by IL-2 knockout and colitis and anemia by Fas mutation.

摘要

This thesis addresses the interaction between the Il2 and fas genes in autoimmune disease, anemia, and ulcerative colitis. A defect in the fas gene causes lpr mice to develop a systemic lupus erythematosis (SLE)-like disease. Auto-reactive T cells, which cannot be depleted due to a lack of Fas-mediated apoptosis, are responsible for autoimmune disease in lpr mice. Interleukin (IL)-2 knockout (Il2−/−) mice develop severe anemia and ulcerative colitis, two contributors to their early lethality. Causes of anemia in Il2−/− mice are not well understood. Infiltration of pathogenic T cells responding to intestinal flora results in colitis. When the Il2 null gene was introduced into lpr mice, the resulting Il2−/− lpr double mutant mice survived the lethality imposed by either gene defect alone and lived longer than both lpr and Il2−/− mice. The Il2−/− lpr mice neither accumulated the abnormal double negative (DN) T cells nor developed a SLE-like autoimmune disease. These mice did not develop anti-dsDNA autoantibodies or immune complex-based glomerulonephritis. Although inflammation was present in the colon, the general architecture remained intact and the apoptosis of epithelial cells observed in Il2 −/− mice was inhibited. Anemia was also dramatically alleviated in Il2−/−lpr mice.; This study establishes three major points. First, IL-2 is a critical cytokine required for the expansion of the abnormal DN T cells and auto-reactive T cells responsible for SLE-like autoimmune disease. Second, colon-infiltrating CD4+ T cells in Il2−/− mice express FasL, causing colonic epithelial cell apoptosis and organ failure. Third, a Fas-mediated mechanism is involved in the development of anemia in Il2−/− mice.; Although apparently healthy, Il2−/− lpr mice, like Il2−/− mice, are deficient in CD4+CD25 + regulatory T cells. Such cells require IL-2 for their development and are important regulators in autoimmune disease and colitis. The present study suggests that IL-2 and Fas act at stages distinct from the stage at which regulatory T cells act. It demonstrates that IL-2 acts at the expansion phase of auto-reactive T cells and that Fas acts at the effector phase of intestine-infiltrating T cells. Finally, this study implicates IL-2 and Fas as potential targets for immunotherapy against SLE and ulcerative colitis, respectively.