Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Aoba-ku, Yokohama, 227-0033, Japan.
Int Immunopharmacol. 2011 Mar;11(3):366-72. doi: 10.1016/j.intimp.2010.10.005. Epub 2010 Oct 16.
Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) receptor modulator, inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs and is highly effective in experimental autoimmune encephalomyelitis (EAE) in mice. In this study, we directly compared the therapeutic effects of FTY720 and recombinant mouse interferon (rm-IFN)-β on relapse and progression of EAE in mice. When FTY720 at oral dose of 0.03 to 1 mg/kg was administered daily after establishment of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice, relapse of EAE was significantly inhibited during administration period. Subcutaneous injection of rm-IFN-β (10,000 IU/mouse) also inhibited the relapse of EAE at early period; however EAE was relapsed in all the mice within administration period. Therapeutic administration of FTY720 (0.03 to 1 mg/kg) significantly improved the symptoms of chronic EAE induced by myelin oligodendrocyte glycoprotein in C57BL/6 mice whereas rm-IFN-β (10,000 IU/mouse) showed no clear effect. These results indicate that FTY720 is more efficacious in mouse EAE as compared with rm-IFN-β. FTY720 markedly reduced the frequency of PLP-specific Th17 and Th1 cells in the spinal cord of EAE mice. On the contrary, FTY720 increased the frequency of PLP-specific Th17 and Th1 cells in the inguinal lymph nodes, suggesting inhibition of egress of myelin antigen-specific Th cells from draining lymph nodes. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of myelin antigen-specific Th17 and Th1 cells into the central nervous system.
芬戈莫德（FTY720），一种鞘氨醇 1-磷酸（S1P）受体调节剂，抑制 S1P 依赖性淋巴细胞从次级淋巴器官中迁出，在实验性自身免疫性脑脊髓炎（EAE）的小鼠模型中具有很高的疗效。在本研究中，我们直接比较了 FTY720 和重组鼠干扰素（rm-IFN）-β对 EAE 小鼠疾病复发和进展的治疗效果。当 SJL/J 小鼠用髓鞘蛋白脂蛋白（PLP）诱导 EAE 后，每天给予 FTY720 口服剂量为 0.03 至 1mg/kg 时，在治疗期间，EAE 的复发得到了显著抑制。皮下注射 rm-IFN-β（10000IU/只）也能在早期抑制 EAE 的复发；然而，所有小鼠在治疗期间均出现 EAE 复发。FTY720（0.03 至 1mg/kg）的治疗性给药显著改善了 C57BL/6 小鼠由髓鞘少突胶质细胞糖蛋白诱导的慢性 EAE 的症状，而 rm-IFN-β（10000IU/只）则没有明显效果。这些结果表明，FTY720 在小鼠 EAE 中的疗效优于 rm-IFN-β。FTY720 显著降低了 EAE 小鼠脊髓中 PLP 特异性 Th17 和 Th1 细胞的频率。相反，FTY720 增加了腹股沟淋巴结中 PLP 特异性 Th17 和 Th1 细胞的频率，表明抑制了髓鞘抗原特异性 Th 细胞从引流淋巴结中的迁出。从这些结果可以看出，FTY720 对 EAE 的改善作用可能是由于减少了髓鞘抗原特异性 Th17 和 Th1 细胞浸润中枢神经系统所致。
