Immunomodulation of inflammatory disease by atorvastatin

描述（由申请人提供）：研究表明，降低胆固醇的3-羟基3-甲基戊二酰辅酶A （HMG-CoA）还原酶抑制剂（“他汀类药物”）具有免疫调节特性，可能有益于治疗th1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偏倚，并促进了Th2细胞的分化，将保护作用过继地传递给未治疗的小鼠。停用阿托伐他汀后EAE保护持续存在，表明阿托伐他汀治疗诱导了持续的免疫调节（耐受）。甲基戊酸，HMG-CoA还原酶的产物，可以阻止阿托伐他汀诱导的Th0细胞向Th2分化。甲羟戊酸途径包括一系列分支酶促反应，这些分支导致产生不同的类异戊二烯化合物，包括多酚、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（异戊二烯化）。因此，甲羟戊酸途径对细胞周期的进展和分化至关重要。我们假设类异戊二烯代谢物是Thl分化所必需的，他汀类药物通过抑制特定甲羟戊酸代谢物的产生来介导Th2分化。我们假设阿托伐他汀诱导的Th2细胞会介导旁观者抑制。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。具体目的是：(1)确定甲羟戊酸分支通路中哪些代谢物影响T细胞的激活和分化，并研究阿托伐他汀和其他类异戊二烯代谢选择性抑制剂如何影响T细胞分化过程中的信号传导和基因转录。(2)基因微阵列将用于鉴定可能被阿托伐他汀改变的免疫调节靶点。(3)我们将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，并通过自身抗原微阵列抑制抗体扩散。这些研究对使用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.