多發(fā)性硬化（Multiple sclerosis,，MS）是一種與神經(jīng)系統(tǒng)相關(guān)的自身免疫性疾病,，是僅次于創(chuàng)傷的中青年人致殘原因,，目前尚缺乏有效的治療藥物,，有著“死不了的癌癥”之稱,。博士生張菲菲等在研究老藥在自身免疫病中的新用途時發(fā)現(xiàn), 金精三羧酸（Aurintricarboxylic acid, ATA）對MS的動物模型EAE小鼠有著顯著的治療效果,。有報道稱金精三羧酸可以通過抑制核酸與蛋白的相互作用,，從而抑制核糖核酸酶及拓撲異構(gòu)酶等；也有報道稱其可以抑制病毒的復制,。金精三羧酸在生物實驗中一般被用于抑制蛋白合成,；其銨鹽（aluminon，鋁試劑）也可用于檢測水、組織及食品中的鋁含量,。
研究發(fā)現(xiàn),，雖然ATA可以有效降低EAE發(fā)病，但它在體外并不直接抑制T細胞的分化,。在體內(nèi),，ATA通過阻斷樹突狀細胞向二級淋巴器官的歸巢，從而抑制T細胞的分化,。我們還發(fā)現(xiàn)ATA也能阻斷致病性T細胞向中樞神經(jīng)系統(tǒng)的浸潤,，并抑制過繼性EAE的發(fā)生。免疫細胞的遷移很大程度上受趨化因子及其受體的調(diào)控,。趨化因子受體屬于G蛋白偶聯(lián)受體（GPCR）家族,，在發(fā)育、炎癥,、腫瘤遷移等方面其重要作用,。研究發(fā)現(xiàn)ATA可以有效抑制許多趨化因子受體（包括CCR4，5,，6,，7，9,，CXCR4,，5，6等）介導的細胞信號轉(zhuǎn)導及細胞遷移,，而對其他GPCR無明顯抑制作用,。趨化因子受體抑制劑在自身免疫病中的作用也一直受到關(guān)注，然而由于趨化因子受體家族龐大,，且功能有重復,，單個受體的抑制往往療效有限。如ATA這類可以同時抑制多種趨化因子受體的化合物在藥物開發(fā)中可能會有更好的前景,。上述成果于12月24日在線發(fā)表在Journal of Immunology上,。
本研究工作是在中科院上海藥物所謝欣研究員指導下完成。謝欣研究員主要從事基于GPCR的新藥發(fā)現(xiàn)及機制研究,，以及小分子化合物調(diào)控干細胞命運的研究,。研究組在近期報道了半胱氨酸白三烯受體及A2B腺苷受體都可作為抗MS藥物開發(fā)的新靶點(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,、自然科學基金委,、科技部以及上海市科委項目的支持。(生物谷Bioon.com)
doi: 10.4049/jimmunol.1201994
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PMID:
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.
