Immunomodulation of inflammatory disease by atorvastatin

描述(申请人提供)：研究表明，降胆固醇的3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(“他汀类”)具有免疫调节特性，可能有益于Th1介导的自身免疫性疾病的治疗。口服阿托伐他汀(立普妥)可以预防或逆转持续复发或慢性EAE。阿托伐他汀治疗诱导了与STAT6磷酸化相关的Th2偏向，并促进了Th2细胞的分化，从而过继地将保护转移到未处理的小鼠。停用阿托伐他汀后，EAE保护作用持续存在，提示阿托伐他汀治疗诱导了持续的免疫调节(耐受)。HMG-CoA还原酶产物甲伐他酸可阻断阿托伐他汀诱导Th0细胞向Th2细胞分化。甲羟戊酸途径涉及与分支的一系列酶反应，导致不同的异戊二烯类化合物的产生，包括多糖醇、泛醌和胆固醇，以及参与信号转导的小GTP结合蛋白(如ras)的翻译后修饰(异戊二烯基化)。因此，甲氧戊酸途径对细胞周期进程和分化至关重要。我们假设类异戊二烯代谢产物是Th1分化所必需的，他汀类药物通过抑制甲氧戊酸代谢产物的产生来调节Th2分化。我们假设阿托伐他汀诱导的Th2细胞将介导旁观者抑制。我们建议研究某些阿托伐他汀诱导的调节性细胞因子在EAE保护中的作用。这些研究将阐明阿托伐他汀诱导免疫调节的机制以及甲氧戊酸途径在T细胞分化和调节中的作用。其具体目的是：(1)确定甲氧戊酸分支途径中的哪些代谢物影响T细胞的激活和分化，并研究阿托伐他汀和其他异戊二烯代谢选择性抑制剂在T细胞分化过程中如何影响信号和基因转录。(2)基因芯片将用于识别阿托伐他汀可能改变的免疫调节中的其他靶点。(3)研究阿托伐他汀治疗是否诱导旁观者抑制，阻止T细胞表位扩散，并利用自身抗原芯片抑制抗体扩散。这些研究对他汀类药物在自身免疫性疾病治疗中的应用具有直接和即时的适用性。

DESCRIPTION (provided by applicant): Studies indicate that cholesterol-lowering 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") have immunomodulatory properties that may be beneficial in treatment of Th1-mediated autoimmune diseases. Oral atorvastatin (Lipitor) could either prevent or reverse ongoing relapsing or chronic EAE. Atorvastatin treatment induced a Th2 bias that was associated with STAT6 phosphorylation, and promoted differentiation of Th2 cells that adoptively transferred protection to untreated mice. EAE protection persisted after atorvastatin was discontinued, suggesting that atorvastatin treatment induced sustained immunomodulation (tolerance). Mevalonic acid, the product of HMG-CoA reductase, prevented both atorvastatin-induced Th2 differentiation by Th0 cells. The mevalonate pathway involves sequences of enzymatic reactions with branches that lead to the production of different isoprenoid compounds including dolichols, ubiquinone and cholesterol, as well as the postranslation modification (isoprenylation) of small GTP binding proteins (e.g. ras) involved in signal transduction. Thus, the mevalonate pathway is crucial for cell cycle progression and differentiation. We hypothesize that isoprenoid metabolites are necessary for Thl differentiation and that statins mediate Th2 differentiation by inhibiting production of specific mevalonate metabolites. We hypothesize that atorvastatin-induced Th2 cells will mediate bystander suppression. We propose to investigate the role of certain atorvastatin-induced regulatory cytokines in EAE protection. These studies will elucidate the mechanisms involved in atorvastatin-induced immunomodulation and role of the mevalonate pathway in T cell differentiation and regulation. The Specific Aims are: (1) To identify which metabolites in the branched mevalonate pathway influence T cell activation and differentiation and examine how atorvastatin and other selective inhibitors in isoprenoid metabolism influence signaling and gene transcription during T cell differentiation. (2) Gene microarray will be used to identify additional targets in immunodulation that may be altered by atorvastatin. (3) We will examine whether atorvastatin treatment induces bystander suppression, prevents epitope spreading of T cells and, using autoantigen microarray, inhibits spreading of antibodies. These studies have direct and immediate applicability to the use of statins in treatment of autoimmune disease.