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目的 观察新型免疫抑制剂FTY72 0对自发性系统性红斑狼疮 (SLE)动物模型BXSB小鼠的治疗作用 ,并用cDNA芯片从基因表达调控角度全局性地初步考察FTY72 0可能作用的免疫通路。方法 BXSB小鼠给予FTY72 0每次 10mg/kg灌胃 ,每周 2次 ;从 9周龄起点动态评估血清IFANA滴度和肾脏组织病理学改变。用cDNA芯片检测脾脏单个核细胞基因表达谱。结果 FTY72 0能够降低处理组BXSB模型血清的IFANA滴度 (P <0 0 5 ) ,FTY72 0对BXSB模型小鼠免疫复合物型肾小球肾炎有明显的抑制作用。脾脏单个核细胞基因表达谱筛选到差异表达基因 2 4 7个 ,包括一批与细胞移行相关的、参与细胞骨架调节的基因。结论 FTY72 0能够对BXSB狼疮模型起到抑制作用。表达谱数据支持FTY72 0主要是通过激活鞘氨醇 1 磷酸 (sphingosine 1 phosphate,S1P)受体从而加速淋巴细胞重新分布的作用机制 ,并提示该通路可能需要Rho蛋白和钙调蛋白参与。FTY72 0可能成为区别于细胞毒免疫抑制剂的新的SLE治疗药物。
Objective To observe the therapeutic effect of novel immunosuppressant FTY72 0 on BXSB mice of spontaneous systemic lupus erythematosus (SLE) and to investigate the possible immunological pathways of FTY72 0 by using cDNA microarray from the perspective of gene expression regulation. Methods BXSB mice were given FTY72 orally at a dose of 10 mg / kg orally twice a week. Serum IFANA titers and renal pathological changes were dynamically evaluated from the 9th week of age. Spleen mononuclear cell gene expression profile was detected by cDNA microarray. Results FTY72 0 could reduce the IFANA titer of BXSB model serum (P <0 05), and FTY72 0 could significantly inhibit the immunocomplex glomerulonephritis of BXSB model mice. Splenic mononuclear cell gene expression profiles were screened for 247 differentially expressed genes, including a number of genes involved in cell migration involved in cytoskeletal regulation. Conclusion FTY72 0 can inhibit the BXSB lupus model. Expression profiling data support FTY72 0 mainly accelerates lymphocyte redistribution by activating sphingosine 1 phosphate (S1P) receptors and suggests that Rho and calmodulin may be involved in this pathway. FTY72 0 may become a new SLE therapeutic agent that is different from cytotoxic immunosuppressive agents.