多发性硬化（Multiple sclerosis，MS）是一种与神经系统相关的自身免疫性疾病，是仅次于创伤的中青年人致残原因，目前尚缺乏有效的治疗药物，有着“死不了的癌症”之称。博士生张菲菲等在研究老药在自身免疫病中的新用途时发现, 金精三羧酸（Aurintricarboxylic acid, ATA）对MS的动物模型EAE小鼠有着显着的治疗效果。有报道称金精三羧酸可以通过抑制核酸与蛋白的相互作用，从而抑制核糖核酸酶及拓扑异构酶等；也有报道称其可以抑制病毒的复制。金精三羧酸在生物实验中一般被用于抑制蛋白合成；其铵盐（aluminon，铝试剂）也可用于检测水、组织及食品中的铝含量。
研究发现，虽然ATA可以有效降低EAE发病，但它在体外并不直接抑制T细胞的分化。在体内，ATA通过阻断树突状细胞向二级淋巴器官的归巢，从而抑制T细胞的分化。我们还发现ATA也能阻断致病性T细胞向中枢神经系统的浸润，并抑制过继性EAE的发生。免疫细胞的迁移很大程度上受趋化因子及其受体的调控。趋化因子受体属于G蛋白偶联受体（GPCR）家族，在发育、炎症、肿瘤迁移等方面其重要作用。研究发现ATA可以有效抑制许多趋化因子受体（包括CCR4，5，6，7，9，CXCR4，5，6等）介导的细胞信号转导及细胞迁移，而对其他GPCR无明显抑制作用。趋化因子受体抑制剂在自身免疫病中的作用也一直受到关注，然而由于趋化因子受体家族庞大，且功能有重复，单个受体的抑制往往疗效有限。如ATA这类可以同时抑制多种趋化因子受体的化合物在药物开发中可能会有更好的前景。上述成果于12月24日在线发表在Journal of Immunology上。
本研究工作是在中科院上海药物所谢欣研究员指导下完成。谢欣研究员主要从事基于GPCR的新药发现及机制研究，以及小分子化合物调控干细胞命运的研究。研究组在近期报道了半胱氨酸白三烯受体及A2B腺苷受体都可作为抗MS药物开发的新靶点(Journal of Immunology 2011,187:2336-45; Journal of Immunology 2013 Jan 1;190(1):138-46.)。
本研究工作得到中科院、自然科学基金委、科技部以及上海市科委项目的支持。(生物谷Bioon.com)
doi: 10.4049/jimmunol.1201994
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Aurintricarboxylic Acid Ameliorates Experimental Autoimmune Encephalomyelitis by Blocking Chemokine-Mediated Pathogenic Cell Migration and Infiltration
Feifei Zhang*, Wei Wei*, Hui Chai* and Xin Xie*,†
Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by the immune-mediated demyelination and neurodegeneration of the CNS. Overactivation of CD4+ T cells, especially the Th1 and Th17 subpopulations, is thought to be the direct cause of this disease. Aurintricarboxylic acid (ATA), an inhibitor of protein–nucleic acid interaction, has been reported to block with the JAK/STAT signaling pathway that is critical for Th cell differentiation. In this study, we discovered that ATA treatment significantly reduces the clinical score of EAE, but it does not directly inhibit the differentiation of Th1 and Th17 cells in vitro. ATA was found to block the chemotaxis and accumulation of dendritic cells in the spleen of EAE mice before the onset of the disease and to reduce the percentage of Th1 and Th17 cells in the spleen. Further study revealed that ATA also blocks the infiltration of pathogenic T cells into the CNS and blocks the onset of passive EAE. ATA was found to inhibit the functions of many chemokine receptors. By blocking chemokine-mediated migration of dendritic cells and pathogenic T cells, ATA alleviates the pathogenesis of EAE and might be used to treat autoimmune diseases, including multiple sclerosis.
