Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide - mechanisms independent of pyrimidine depletion
Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide - mechanisms independent of pyrimidine depletion
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DOI：
10.1189/jlb.0504308
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发表时间：
2004-11-01
影响因子：
5.5
通讯作者：
Jung, S
中科院分区：
文献类型：
--
作者：
Korn, T;Magnus, T;Jung, S
来氟米特抑制新生嘧啶合成，是一种新型免疫抑制剂，已成功用于治疗类风湿性关节炎。在这里，我们研究了来氟米特在实验性自身免疫性脑脊髓炎（EAE）中的疗效及其作用模式，EAE是一种T辅助细胞1型细胞传播疾病模型，用于模拟多发性硬化症的炎症方面，并在Lewis大鼠中通过髓鞘碱性蛋白（MBP）特异性T系细胞过继转移诱导。细胞移植后7天给药，来氟米特抑制了疾病的临床症状，即使在尿嘧啶替代的动物中也是如此。在A77 1726（来氟米特的活性代谢物）存在的情况下，体外抗原激活的mbp特异性T细胞产生较少的干扰素- γ，而白细胞介素(IL)-10的分泌有增加的趋势，而信号转导和转录转运激活因子没有变化。此外，这些T细胞表现出降低的趋化性，并在转移到幼稚大鼠后显著减轻了疾病病程。来氟米特对体外mbp特异性记忆型T系细胞的影响可能不是由嘧啶耗竭介导的，因为它们不能被外源性尿嘧啶逆转。此外，A77 1726导致体外培养的小胶质细胞中CD86 （B7-2）的表达和IL-10的分泌增加，增强了它们对活化的自身抗原特异性T细胞的下调作用。总之，我们的观察强调来氟米特对EAE效应细胞的免疫调节潜力具有临床相关性，并不完全依赖于细胞嘧啶池的消耗。
Leflunomide inhibits de novo pyrimidine synthesis and is a novel, immunosuppressive agent that has been successfully used to treat rheumatoid arthritis. Here, we investigated the efficacy of leflunomide and its mode of action in experimental autoimmune encephalomyelitis (EAE), which is a T helper cell type 1 cell-borne disease model to simulate inflammatory aspects of multiple sclerosis and was induced in Lewis rats by adoptive transfer of myelin basic protein (MBP)-specific T line cells. Given in vivo for 7 days after cell transfer, leflunomide suppressed clinical signs of disease even in uridine-substituted animals. MBP-specific T line cells that had been antigen-activated in vitro in the presence of A77 1726 (active metabolite of leflunomide) produced less interferon-gamma, whereas interleukin (IL)-10 secretion had a tendency to be increased without changes in signal transducer and activator of transcription 6 trafficking. Furthermore, these T cells exhibited reduced chemotaxis and induced a significantly mitigated disease course upon transfer into naive rats. The effects of leflunomide on MBP-specific memory type T line cells in vitro may not be mediated by pyrimidine depletion, as they were not reversible by exogenous uridine. Moreover, A77 1726 led to increased expression of CD86 (B7-2) and secretion of IL-10 in cultured microglial cells in vitro, strengthening their down-modulatory impact on activated, autoantigen-specific T cells. In conclusion, our observations underline that the immunomodulatory potential of leflunomide in effector cells of EAE is clinically relevant and is not exclusively dependent on the depletion of cellular pyrimidine pools.