Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats.
Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats.
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Leflunomide在Lewis大鼠中对实验性自身免疫性葡萄膜炎的改善。
DOI：
10.1371/journal.pone.0062071
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Fang CB;Zhou DX;Zhan SX;He Y;Lin Z;Huang C;Li J
探讨来氟米特对大鼠实验性自身免疫性葡萄膜炎(EAU)的治疗作用。用光感受器间维甲酸结合肽(IRBP)免疫Lewis大鼠，制备EAU。大鼠在3个剂量(3 mg/kg/d；6 mg/kg/d；12 mg/kg/d)免疫后，分别灌胃给予来氟米特(预防或治疗方案)。给予环孢素A作为阳性对照。在疾病活动高峰期(第14天或第15天)处死大鼠。实验终止后，通过临床EAU评分(D14)和眼球摘除后的组织病理学评价来评估治疗效果。用双抗体夹心法测定血清中炎性细胞因子的表达水平。取大鼠眼球，用RT-PCR法测定白介素17(IL17)和干扰素-γ的表达。用流式细胞仪检测活化的CD4(+)T细胞内IL-17的表达。在分离的淋巴细胞中观察来氟米特对大鼠免疫反应的影响。组织病理学和临床资料显示免疫大鼠眼内炎症严重。在此EAU模型中，炎症在第14天达到顶峰。来氟米特治疗显著预防和治疗EAU引起的眼部炎症，并降低临床和病理评分，与赋形剂治疗眼相比。来氟米特治疗眼IL-17和干扰素-γ基因表达明显降低。来氟米特可显著降低血清IL-17和干扰素-γ水平。用流式细胞仪检测外周血和脾组织中IL17+T细胞的变化，发现来氟米特干预组大鼠外周血和脾组织中Th17细胞数量明显减少。来氟米特处理的动物的淋巴细胞在体外与未处理的动物的淋巴细胞相比，抗原特异性增殖能力降低。来氟米特可有效抑制IRBP诱导的大鼠葡萄膜炎。这些结果提示来氟米特可能在葡萄膜炎中有潜在的临床应用价值。
To investigate the efficacy of leflunomide in experimental autoimmune uveitis (EAU) in rats. Lewis rats were immunized with interphotoreceptor retinoid-binding peptide (IRBP) in order to generate EAU. Rats received three dose of leflunomide through intragastric administration (prevention or treatment protocols) after immunization at three separate doses (3 mg/kg/d; 6 mg/kg/d; 12 mg/kg/d). Cyclosporin A was administered as a positive) control. Rats were euthanized during peak disease activity (day 14 or 15). Treatment effectiveness was evaluated in vivo using clinical EAU scoring (d14) and histopathological evaluation of enucleated eyes after experimental termination. The expression levels of inflammatory cytokines in the serum were quantified by ELISA. Eyeball of rats were harvested and mRNA expression of interleukin 17 (IL17) and IFN-γ were quantified through RT-PCR. Intracellular expression of interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. The effects of leflunomide inhibition on immune responses in rats were investigated in isolated lymphocytes. Histopathological and clinical data revealed severe intraocular inflammation in the immunized rat. Inflammation reached its peak on day 14 in this EAU model. Treatment with leflunomide significantly prevented and treated EAU-induced ocular inflammation and decreased clinical and pathological scores compared to vehicle-treated eyes. Gene expression of IL17 and IFN-γwas markedly reduced in leflunomide-treated eyes. Leflunomide significantly decreased the serum levels of IL17 and IFN-γ. The study of IL17+ T cells in peripheral blood and spleen by flow cytometry showed a decreased number of Th17 cell in rats of leflunomide prevented group. Lymphocytes from animals treated with leflunomide had decreased antigen-specific proliferation in vitro compared with lymphocytes from untreated animals. Oral administration of leflunomide effectively suppressed IRBP-induced uveitis in rats. These results suggest that leflunomide may be potentially clinical application in uveitis.
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作者：
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通讯作者：
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