Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis?
Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis?
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DOI：
10.1093/intimm/dxh394
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Vollmer, TL
中科院分区：
文献类型：
--
作者：
Jee, Y;Liu, RL;Vollmer, TL
醋酸格拉替雷（GA）对多发性硬化（MS）患者临床获益的潜在机制仍然难以捉摸。一个流行的假设是，GA可以诱导T（h）2极化T细胞，其交叉识别髓鞘特异性表位，并可以抑制T（h）1 T细胞中的髓鞘反应性自身攻击，这一过程称为“旁观者抑制”。为了测试GA的功效是否确实由T（h）2 T细胞介导，我们利用了MS的动物模型：C57 BL/6小鼠中的实验性自身免疫性脑脊髓炎（EAE）。GA治疗对EAE具有中度保护作用。来自这些小鼠的GA反应性T细胞不是T（h）2极化的，并且GA处理的小鼠中髓鞘反应性T细胞的T（h）1细胞因子减少与未处理的对照小鼠相当。值得注意的是，GA在IL-4、IL-10缺陷和IL-4/IL-10双缺陷小鼠中也观察到对EAE的保护作用。与野生型小鼠相似，IL-4和IL-10缺陷小鼠中的GA治疗与髓磷脂反应性T细胞扩增减少和髓磷脂抗原诱导的IFN-γ和肿瘤坏死因子-α的产生减少相关。因此，尽管缺乏两种主要的T（h）2细胞因子IL-4和IL-10，单独或组合，GA仍然有益于抑制EAE。我们的研究结果警告的概念，T（h）2细胞和旁观者抑制帐户GA对EAE的影响，并建议一种替代机制可能会在GA治疗MS患者。
Mechanisms underlying the clinical benefits of glatiramer acetate (GA) for patients with multiple sclerosis (MS) remain elusive. A prevailing hypothesis is that GA can induce T(h)2-polarized T cells, which cross-recognize myelin-specific epitopes and can inhibit myelin-reactive autoaggression in T(h)1 T cells, a process referred to as 'bystander suppression.' To test whether the efficacy of GA is indeed mediated by T(h)2 T cells, we have utilized an animal model for MS: experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. GA therapy conferred moderate protection from EAE. GA-reactive T cells from these mice were not T(h)2 polarized, and the T(h)1 cytokine reduction of myelin-reactive T cells in GA-treated mice was comparable to that in untreated control mice. Significantly, the protective effects of GA against EAE were also observed in IL-4-, IL-10-deficient and IL-4/IL-10 double-deficient mice. Similar to wild-type mice, GA therapy in IL-4- and IL-10-deficient mice was associated with diminished myelin-reactive T cell expansion and reduced production of myelin antigen-induced IFN-gamma and tumor necrosis factor-alpha. Thus, despite the absence of two prominent T(h)2 cytokines, IL-4 and IL-10, either alone or combined, GA was still beneficial in suppressing EAE. Our results caution against the notion that T(h)2 cells and bystander suppression account for the effect of GA on EAE and suggest that an alternative mechanism may operate in GA-treated MS patients.