Immunomodulation of inflammatory disease by atorvastatin

描述（由申请人提供）：研究表明，降胆固醇3-羟基3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（“他汀类药物”）具有免疫调节特性，可能有益于治疗Th 1介导的自身免疫性疾病。口服阿托伐他汀（立普妥）可以预防或逆转正在进行的复发性或慢性EAE。阿托伐他汀治疗诱导了与STAT 6磷酸化相关的Th 2偏倚，并促进了Th 2细胞的分化，这些细胞过继性地将保护转移给未治疗的小鼠。阿托伐他汀停药后EAE保护作用持续存在，表明阿托伐他汀治疗诱导了持续的免疫调节（耐受）。甲羟戊酸，HMG-CoA还原酶的产物，阻止阿托伐他汀诱导的Th 0细胞的Th 2分化。甲羟戊酸途径涉及具有分支的酶促反应序列，其导致产生不同的类异戊二烯化合物，包括长萜醇、泛醌和胆固醇，以及参与信号转导的小GTP结合蛋白（例如ras）的翻译后修饰（异戊二烯化）。因此，甲羟戊酸途径对细胞周期进展和分化至关重要。我们假设类异戊二烯代谢物是Th 1分化所必需的，他汀类药物通过抑制特异性甲羟戊酸代谢物的产生来介导Th 2分化。我们假设阿托伐他汀诱导的Th 2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的免疫调节机制以及甲羟戊酸途径在T细胞分化和调节中的作用。具体目标是：（1）鉴定分支甲羟戊酸途径中的哪些代谢物影响T细胞活化和分化，并检查阿托伐他汀和类异戊二烯代谢中的其他选择性抑制剂如何影响T细胞分化期间的信号传导和基因转录。(2)基因微阵列将用于确定其他目标，在免疫调节，可能会改变阿托伐他汀。(3)我们将检查阿托伐他汀治疗是否诱导旁观者抑制，防止T细胞表位扩散，并使用自身抗原微阵列，抑制抗体的扩散。这些研究对他汀类药物治疗自身免疫性疾病具有直接和立即的适用性。

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.