OMEGA 3 LIPIDS AND CALORIES EFFECT ON SLE AND AGING

自身免疫易感性NZBxNZW F1（B/W）小鼠是一种有用的 系统性红斑狼疮（SLE）。 中度热量限制（CR） 延缓了疾病的发作，使这些动物的寿命延长了一倍。 CR和富含鱼油（w-3）脂肪酸的饲料均降低 炎性细胞因子，维持（CD 4 + CD 44低）T细胞亚群， 防止记忆（CD 4 +/CD 44 High）T细胞随年龄增长而增加。 的 Th-1和Th-2 T细胞亚群在慢性粒细胞白血病发病机制中的作用 鼠（可能还有人）狼疮引起了一个问题，即CR和 w-3补充剂通过调节抗- 炎性细胞因子 我们建议，CR延迟分化 CD 44高T细胞通过维持Th-0和/或Th-1和Th-2亚群 更高水平的肾上腺皮质类固醇（CORT）水平和细胞凋亡。 在 此外，w-3脂质和CR也可能影响共刺激分子 通过增加抗氧化酶的表达， 氧化应激 我们建议补充w-3脂肪酸 与CR结合，通过减少免疫系统的老化， 自由基和炎性细胞因子的形成以及B减少 细胞自身抗体产生。 我们假设CR延迟形成 Th-1/Th-2亚群的共刺激相互作用，包括降低 CD 40配体表达和正常化的细胞凋亡，在两个淋巴 细胞和靶组织。 具体目标1中的研究将确定 有和没有CR的玉米油与鱼油脂质影响 Th-1和Th-2细胞的分化途径和功能活性 通过调节CD 28/CTLA-4和B7-1/B7-2共刺激分子之间的相互作用， CD 4 + T细胞和B细胞中的刺激分子。 实验 具体目标2将确定W-3脂肪延长寿命 酸和/或CR伴有抗CD 3或地塞米松增加 诱导胸腺和脾细胞凋亡。专项研究 3将决定是否延长寿命的w-3脂肪酸 和/或CR伴有B/W中自身抗体产生减少 小鼠 总之，我们的研究将检查w-3脂肪酸是否 联合中度CR可进一步改善 B/W小鼠。 这些研究尤其重要，因为 近年来，植物油的消费量显著增加 这可能会促进美国的肥胖和自身免疫性疾病。 在 相反，抗炎的w-3脂肪酸被消耗， 可忽略不计的金额。 适度的饮食改变可能会 延缓自身免疫性疾病的发作， 所需剂量的细胞毒性和免疫抑制药物通常 用于治疗SLE和其他自身免疫性疾病。

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.