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Analysis on Mechanism of Development of Collagen Diseases Through Apoptosis

细胞凋亡导致胶原病发生的机制分析

基本信息

批准号：
13670468
负责人：
OKAZAKI Hitoaki
金额：
$ 2.3万
依托单位：
Jichi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670468/
关键词：
Apoptosis FTY720 Ceramide NZB W F1 Systemic lupus erythematosus DBA 1 Rheumatoid arthritis C2-セラミド W F1マウス全身性エリテマトーデス(SLE)

项目摘要

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.

目的：我们已经证明，新型免疫抑制剂FTY720对MRL-LPR/LPR小鼠的治疗可以改善肾小球肾炎，延长该菌株的生存期。在这项研究中，我们评估了FTY720对另一种实验性系统性红斑狼疮(SLE)小鼠-雌性NZBxNZWF1(B/W F1)的影响。方法：自8月龄起，12只雌性B/W F1小鼠分别口服FTY720、甲基强的松龙(MPSL)或赋形剂，每周3次。以血清抗dsDNA抗体水平和生存率为指标评价治疗效果。结果FTY720可显著减少CD5+B细胞的数量，抑制抗dsDNA抗体的产生(FTY720vs11月龄对照组：213±88U/mlvs509±196U/mlp&lt；0.05)，并减少肾小球内IgG的沉积。在13个月龄时，FTY720组小鼠的存活率为75.0%，而对照组为25.0%(p&lt；0.01)。结论FTY720可抑制雌性B/W F1小鼠的自身免疫反应，延长其死亡时间。对自身免疫的抑制没有明显的副作用。因此，它可用于人类系统性红斑狼疮的主要或辅助治疗。