Analysis on Mechanism of Development of Collagen Diseases Through Apoptosis

目的：我们已经证明用FTY 720（一种新型免疫抑制剂）治疗MRL-lpr/lpr小鼠，可以改善肾小球肾炎并延长该品系小鼠的寿命。在这项研究中，我们评估了FTY 720的影响，对系统性红斑狼疮（SLE）的额外的实验小鼠模型，女性NZBxNZWF 1（B/WF 1）。方法：自8个月大，12只女性B/WF 1小鼠接受口服2毫克/公斤的FTY 720，甲泼尼龙（mPSL）或车辆，每周三次。以血清抗dsDNA抗体水平和生存率评价疗效。结果：FTY 720能显著降低腹腔CD 5 ^+ B细胞的数量，抑制抗dsDNA抗体的产生，并能显著抑制CD 5 ^+ B细胞的增殖，抑制CD 5 ^+ B细胞的增殖，抑制CD 5 ^+ B细胞的增殖（FTY 720对对照：11月龄时213± 88 U/ml对509± 196 U/ml，p<0.05），并且与对照动物相比减少了肾小球中IgG的沉积。在13月龄时，FTY 720治疗的小鼠的存活率为75.0%，而对照组为25.0%（p<0.01）。结论：FTY 720可抑制B/W F1小鼠自身免疫性疾病的发生，延长小鼠寿命。抑制自身免疫，实现了没有明显的副作用。因此，它可能是有用的人SLE的初级或后续治疗。

Objectiv.We have shown that treatment of MRL-lpr/lpr mice whh FTY720, a novel immunosuppressant, ameliorates glomerulonephritis and prolongs the liie-span of this strain. In this study, we evaluated the effects of FTY720, on an additional experimental murine model of systemic lupus erythematosus (SLE) ; the female NZBxNZWF1 (B/W F1).Methods.Since 8 months of age, 12 female B/W F1 mice received oral 2 mg/kg each of FTY720, methylprednisolone (mPSL) or vehicle, three times in week. Therapeutic efficacy was evaluated by levels of anti-dsDNA antibodies in serum and the survival rate. In parallel, phenotypes of splenocytes, peritoneal exudates cells and bone marrow cells, as well as immunohistochemistry of the kidney, were examined.Results.FTY720 significantly reduced the number of CD5^+ B cells from the peritoneal cavity, suppressed the production of anti-dsDNA antibodies (FTY720 vs control : 213±88U/ml vs 509±196U/ml at 11 months of age, p<0.05) and decreased the deposition of IgG in glomeruli from compared to control animals. At 13 months of age, the survival rate in the FTY720-treated mice was 75.0% compared to 25.0% in controls (p<0.01). Administration of FTY720 produced no adverse effects, such as liver dysfunction, or hyperglycemia seen in the mPSL-treated mice.Conclusion.FTY720 suppressed the development of autoimmunity and prolonged die lifespan of female B/W F1 mice. Suppression of autoimmunity was achieved without obvious side effects. Hence, it could be useful for primaiy or adjunctive therapy of human SLE.