The Complement Inhibitor FUT-175 Suppresses T Cell Autoreactivity in Experimental Autoimmune Encephalomyelitis
The Complement Inhibitor FUT-175 Suppresses T Cell Autoreactivity in Experimental Autoimmune Encephalomyelitis
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补体抑制剂 FUT-175 可抑制实验性自身免疫性脑脊髓炎中的 T 细胞自身反应性。
DOI：
10.2353/ajpath.2009.081093
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发表时间：
2009-08-01
影响因子：
6
通讯作者：
Lin, Feng
中科院分区：
文献类型：
--
作者：
Li, Qing;Nacion, Kristine;Lin, Feng
最近的几项研究表明，相互作用的抗原呈递细胞和/或T细胞产生补体活化产物C5 a和C3 a，整体参与T细胞活化，并促进实验性自身免疫性脑脊髓炎（多发性硬化的啮齿动物模型）中髓鞘少突胶质细胞糖蛋白（MOG（35-55））特异性干扰素-γ和白细胞介素-17产生T细胞的产生。在这项研究中，我们测试了FUT-175，一种已被证明可以抑制C3/C5转化酶形成的临床药物，是否可以减弱髓鞘特异性T细胞反应，以及实验性自身免疫性脑脊髓炎的疾病严重程度。在体外，FUT-175通过抗原呈递细胞-T细胞复合物抑制局部C5 a/C3 a产生，并减弱MOG（35-55）特异性Th 1和Th 17应答，几乎没有非特异性细胞毒性。FUT-175的体内给药延迟了实验性自身免疫性脑脊髓炎疾病的发作，降低了临床评分，减少了中枢神经系统炎症，并减少了脱髓鞘。FUT-175处理的小鼠表现出MOG（35-55）特异性干扰素-γ和白细胞介素-17产生T细胞数量减少。此外，FUT-175处理来自MOG（35-55）免疫小鼠的过继转移脾细胞的幼稚受体的结果表明，FUT-175对MOG特异性细胞应答的影响，而不是对抗MOG抗体的影响。这些结果表明，抑制C5 a/C3 a产生的补体调节剂可能对多发性硬化症和T细胞驱动疾病发病机制的其他临床病症具有治疗功效。
Several recent studies have shown that interacting antigen presenting cells and/or T cells produced complement activation products C5a and C3a, are integrally involved in T-cell activation, and promote the generation of myelin oligodendrocyte glycoprotein (MOG(35-55))-specific interferon-gamma and interleukin-17-producing T cells in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. In this study, we tested whether FUT-175, a clinical pharmaceutical that has been shown to inhibit the formation of C3/C5 convertases, can attenuate myelin-specific T-cell responses, as well as disease severity in experimental autoimmune encephalomyelitis. In vitro, FUT-175 inhibited local C5a/C3a production by antigen presenting cell-T-cell complexes and attenuated MOG(35-55)-specific Th1 and Th17 responses with little nonspecific cytotoxicity. In vivo administration of FUT-175 delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination. The FUT-175-treated mice exhibited decreased numbers of MOG(35-55)-specific interferon-gamma- and interleukin-17-producing T cells. In addition, results from the FUT-175 treatment of naive recipients of adoptively transferred splenocytes from MOG(35-55)-immunized mice suggested that the effect of FUT-175 was on MOG-specific cellular responses and not on anti-MOG antibodies. These results argue that complement regulators, which inhibit C5a/C3a production, may have therapeutic efficacy in multiple sclerosis and in other clinical conditions in which T cells drive disease pathogenesis.