The autoimmune prone NZBxNZW F1 (B/W) mouse is a useful model of systemic lupus erythematosus (SLE). Moderate calorie restriction (CR) delays the onset of disease and doubles the life span of these animals. Both CR and diets enriched in fish oil ((w-3) fatty acids decrease inflammatory cytokines, maintain (CD4+ CD44Low) T cell subsets and prevent the rise of memory (CD4+/CD44High) T cells with age. The involvement of Th-1 and Th-2 T cells subsets in the pathogenesis of murine (and probably human) lupus raises the question of whether CR and w-3 supplementation produce their effects by modulating anti- inflammatory cytokines. We propose that CR delays differentiation of CD44High T cells into Th-0, and/or Th-1 and Th-2 subsets by maintaining higher levels of adrenocorticosteroid (CORT) levels and apoptosis. In addition w-3 lipids and CR may also influence co-stimulatory molecules by increasing expression of antioxidant enzymes and reducing chronic oxidative stress. We propose that supplementation with w-3 fatty acids combined with CR maintains a youthful immune system by decreasing formation of free radicals and inflammatory cytokines and decreasing B cells autoantibody production. We hypothesize that CR delays formation of Th-1/Th-2 subsets by co-stimulatory interaction including lowering CD40 ligand expression and by normalizing apoptosis in both lymphoid cells and target tissues. Studies in specific aim 1 will determine if corn oil vs. fish oil lipids with and without CR affect the differentiation pathways and functional activity of Th-1 and Th-2 cells by modulating the interaction between CD28/CTLA-4 and B7-1/B7-2 co- stimulatory molecules in CD4+ T cells and B cells. Experiments in specific aim 2 will determine if prolongation of life span by w-3 fatty acids and/or CR is accompanied by increased anti-CD3 or dexamethasone induced apoptosis in thymic and splenic cells. Studies in specific aim 3 will determine whether prolongation of lifespan by w-3 fatty acids and/or CR is accompanied by decreased autoantibody production in B/W mice. In summary, our studies will examine whether w-3 fatty acids combined with moderate CR can further ameliorate autoimmune disease in B/W mice. These studies are especially important in view of the significant rise in the consumption of vegetable oils in recent years which may promote obesity and autoimmune disorders in the USA. In contrast, the anti-inflammatory w-3 fatty acids are consumed in negligible amounts. It is possible that moderate dietary changes will delay the onset of autoimmune diseases as well as significantly decrease the required doses of cytotoxic and immunosuppressive drugs normally used to treat SLE and other autoimmune diseases.
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