Basic study concerning the gene therapy using p53 gene toward rheumatoid arthritis

来氟米特是一种免疫调节性药物，已显示出在预防器官移植排斥反应和一系列自身免疫性疾病方面的有效性。为了探讨来氟米特介导的免疫抑制机制，我们在体内观察了来氟米特对抗原刺激的T细胞的影响。来氟米特诱导SEB激活的V-8^+T细胞表达P53。来氟米特还能抑制SEB激活的V-8^+T细胞增殖细胞核抗原和细胞周期蛋白E的表达。我们的数据提示，来氟米特介导的活化T细胞的细胞周期调节可能是来氟米特治疗实现免疫抑制的潜在机制。我们还研究了来氟米特的活性代谢物A771726对IL-1β刺激的类风湿滑膜成纤维细胞丝裂原活化蛋白激酶的影响。观察A771726对类风湿滑膜成纤维细胞分泌基质金属蛋白酶(MMPs)的影响。A771726部分A771726能有效抑制IL-1β刺激的类风湿滑膜成纤维细胞。提示来氟米特抑制类风湿滑膜成纤维细胞MAPK信号通路和MMPs合成可能是其抗类风湿关节炎作用的机制之一。

Leflunomide is an immuneregulatory drug that has shown effectiveness in the prevention of organ graft rejection as well as in an array of autoimmune diseases. In order to explore the mechanism of leflunomide-mediated immunosuppression, we investigated the effects of leflunomide on antigen-stimulated T cells in vivo. Leflunomide induced p53 expression in SEB-activated V□8^+ T cells. Also, increased levels of proliferating cell nuclear antigen (PCNA) and Cyclin E expression of SEB-activated V□8^+ T cells was suppressed by leflunomide. Our data suggest that the leflunomide-mediated cell cycle regulation of activated T cells may present a potential mechanism of immunosuppression achieved by leflunomide treatment. We also investigated the effects of A77 1726, leflunomide's active metabolite, on mitogen-activated protein kinases (MAPK) activation in IL-1β-stimulated rheumatoid synovial fibroblasts. The effects of A77 1726 on the secretion of matrix metalloproteinases (MMPs) from rheumatoid synovial fibroblasts were also examined. A77 1726 partially A77 1726 efficiently suppressed IL-1β-stimulated rheumatoid synovial fibroblasts. Our results suggest that the suppression of MAPK signaling pathway and MMPs synthesis in rheumatoid synovial fibroblats is a possible mechanism for the inhibitory activity of leflunomide against rheumatoid arthritis.