The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis.
The antiepileptic drug valproic acid restores T cell homeostasis and ameliorates pathogenesis of experimental autoimmune encephalomyelitis.
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抗癫痫药物丙戊酸恢复 T 细胞稳态并改善实验性自身免疫性脑脊髓炎的发病机制
DOI：
10.1074/jbc.m112.356584
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发表时间：
2012-08-17
期刊：
影响因子：
--
通讯作者：
Xie X
中科院分区：
文献类型：
--
作者：
Lv J;Du C;Wei W;Wu Z;Zhao G;Li Z;Xie X
背景：T细胞存活和凋亡的失调是包括多发性硬化（MS）在内的自身免疫性疾病的常见原因。结果：丙戊酸（VPA）治疗恢复了失调的T细胞凋亡，减轻了EAE的症状。结论：VPA除具有抗癫痫作用外，还具有调节T细胞稳态的作用。重要性：作为一种口服药物，VPA可用于治疗自身免疫性疾病，如MS。维持恒定的免疫细胞数量和比例是免疫稳态严格调节的一个关键方面。这种平衡的破坏将导致自身免疫性疾病，如多发性硬化症（MS）。据报道，抗癫痫药物丙戊酸（VPA）可调节许多细胞的生长、存活和分化。然而，其在T细胞稳态和MS治疗中的功能仍然未知。在这项研究中，VPA被发现减少脊髓炎症，脱髓鞘，和疾病评分在实验性自身免疫性脑脊髓炎，MS的小鼠模型。进一步的研究表明，VPA诱导活化的T细胞凋亡，并维持免疫稳态。发现这种作用主要由caspase-8/caspase-3途径介导。有趣的是，这种现象也在正常人受试者和MS患者的T细胞中得到证实。考虑到长期的临床使用历史和我们的新发现，我们相信VPA可能是一种安全有效的治疗自身免疫性疾病，如多发性硬化症。
Background: Dysregulation of T cell survival and apoptosis is the common cause of autoimmune diseases including multiple sclerosis (MS). Results: Valproic acid (VPA) treatment restores the dysregulated apoptosis of T cells and reduces the symptoms of EAE. Conclusion: In addition to the antiepileptic activity, VPA also regulates T cell homeostasis. Significance: As an orally available drug, VPA might be used to treat autoimmune diseases, such as MS. Maintaining a constant number and ratio of immune cells is one critical aspect of the tight regulation of immune homeostasis. Breakdown of this balance will lead to autoimmune diseases such as multiple sclerosis (MS). The antiepileptic drug valproic acid (VPA) was reported to regulate the growth, survival, and differentiation of many cells. However, its function in T cell homeostasis and MS treatment remains unknown. In this study, VPA was found to reduce spinal cord inflammation, demyelination, and disease scores in experimental autoimmune encephalomyelitis, a mouse model of MS. Further study indicated that VPA induces apoptosis in activated T cells and maintains the immune homeostasis. This effect was found to be mainly mediated by the caspase-8/caspase-3 pathway. Interestingly, this phenomenon was also confirmed in T cells from normal human subjects and MS patients. Considering the long history of clinical use and our new findings, we believe VPA might be a safe and effective therapy for autoimmune diseases, such as multiple sclerosis.