Vision Institute, Universidade Federal de São Paulo, São Paulo, Brazil.
Invest Ophthalmol Vis Sci. 2010 May;51(5):2568-74. doi: 10.1167/iovs.09-4769. Epub 2009 Dec 17.
FTY720 (fingolimod) is an immunomodulatory drug capable of preventing T-cell migration to inflammatory sites by binding to and subsequently downregulating the expression of sphingosine-1 phosphate receptor 1 (S1P(1)) leading in turn to T-cell retention in lymphoid organs. Additional effects of FTY720 by increasing functional activity of regulatory T cells have recently been demonstrated, raising the conversion of conventional T cells into regulatory T cells and affecting the sequestration of regulatory T cells in normal mice. In this study, the action of FTY720 in the ocular autoimmune model in mice was investigated.
Mice were immunized with 161-180 peptide and pertussis toxin and were treated with 1 mg/kg/d FTY720 by gavage (7-21 days postimmunization [dpi]) or left untreated. Spleen cells, harvested 21 dpi, were cultured and assayed for cytokine production. Draining lymph node, spleen, and eye cells 21 dpi were assayed for quantification of T-cell populations. Disease severity was evaluated by histologic examination of the enucleated eyes at 21 and 49 dpi. In addition, anti-IRBP antibodies were analyzed by ELISA.
FTY720 was effective in suppressing the experimental autoimmune uveitis score. Although there was a reduction in the number of eye-infiltrating cells, FTY did not prevent Treg accumulation at this site. FTY720 leads to a significant increase of CD4(+)IFN-gamma(+) and CD4(+)Foxp3(+) cell percentages in lymph nodes, suggesting that this site could be the source of Treg cells found in the eye.
The data showed that treatment in vivo with FTY720 was able to suppress EAU in mice. These results are indicative of the possible therapeutic use of FTY720 in ocular autoimmune processes.
FTY720（fingolimod）是一种免疫调节剂，通过与鞘氨醇-1-磷酸受体 1（S1P1）结合并随后下调其表达，从而阻止 T 细胞迁移至炎症部位，从而使 T 细胞滞留在淋巴器官中，从而防止 T 细胞迁移到炎症部位。最近已经证明 FTY720 的其他作用是通过增加调节性 T 细胞的功能活性，从而提高常规 T 细胞向调节性 T 细胞的转化，并影响调节性 T 细胞在正常小鼠中的隔离。在这项研究中，研究了 FTY720 在小鼠眼自身免疫模型中的作用。
用 161-180 肽和百日咳毒素免疫小鼠，并通过灌胃（免疫后 7-21 天[dpi]）用 1mg/kg/d FTY720 治疗或不治疗。在 21 dpi 时收获脾细胞，并进行细胞因子产生的培养和测定。在 21 dpi 时测定引流淋巴结、脾脏和眼睛细胞中的 T 细胞群体的定量。通过在 21 和 49 dpi 时对眼球进行组织学检查评估疾病严重程度。此外，通过 ELISA 分析抗 IRBP 抗体。
FTY720 能有效抑制实验性自身免疫性葡萄膜炎评分。尽管眼内浸润细胞数量减少，但 FTY 并未阻止 Treg 在该部位的积聚。FTY720 导致淋巴结中 CD4+IFN-γ+和 CD4+Foxp3+细胞百分比显著增加，提示该部位可能是在眼内发现的 Treg 细胞的来源。
数据表明，体内用 FTY720 治疗能够抑制小鼠的 EAU。这些结果表明，FTY720 可能在眼部自身免疫过程中具有治疗用途。
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