Immunomodulation of inflammatory disease by atorvastatin

阿托伐他汀对炎症性疾病的免疫调节

• 批准号: 6874590
• 负责人: SCOTT S ZAMVIL
• 金额: $ 43.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874590
• 关键词: T lymphocyte; atorvastatin; autoantibody; autoantigens; biological signal transduction; cell differentiation; cytokine; cytoprotection; experimental allergic encephalomyelitis; gene expression; genetic transcription; genetically modified animals; immunomodulators; isoprenoid; laboratory mouse; leukocyte activation /transformation; mevalonate; microarray technology; phosphorylation; polymerase chain reaction; prenylation; western blottings

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.

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（“ Statins”）具有免疫调节性能，可能对TIT1-介导的TH1介导的自身免疫疾病的治疗可能有益。口服阿托伐他汀（Lipitor）可以预防或逆转持续的复发或慢性EAE。 Atorvastatin治疗诱导了与STAT6磷酸化相关的Th2偏置，并促进了Th2细胞的分化，这些细胞通过传递保护向未处理的小鼠。在停止Atorvastatin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（耐受性）。 HMG-COA还原酶的产物甲瓦硅酸甲酸阻止了阿托伐他汀诱导的Th0细胞的Th2分化。甲戊酸途径涉及与分支的酶促序列，这些分支导致产生不同的类异丙醇化合物，包括dolichols，泛氨基酮和胆固醇，以及涉及信号转导的小型GTP结合蛋白（例如，小GTP结合蛋白（例如，小GTP）的poStranslation修饰（异源）。因此，大甲酸酯途径对于细胞周期进程和分化至关重要。我们假设异急动物代谢物对于THL分化是必要的，而他汀类药物通过抑制特定的甲丙酸酯代谢产物的产生来介导Th2分化。我们假设Atorvastatin诱导的Th2细胞会介导旁观者抑制。我们建议研究某些雌雄同体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和甲戊酸途径在T细胞分化和调节中的作用的机制。具体目的是：（1）确定分支的甲戊酸途径中的哪些代谢产物影响T细胞的激活和分化，并检查异戊丁素和其他选择性抑制剂如何在类化代谢中如何影响T细胞分化过程中的基因转录和基因转录。 （2）基因微阵列将用于确定可以通过阿托伐他汀改变的免疫调节中的其他靶标。 （3）我们将检查Atorvastatin治疗是否诱导旁观者抑制，防止表位细胞扩散，并使用自动抗原微阵列抑制抗体的扩散。这些研究对他汀类药物在治疗自身免疫性疾病中具有直接的直接适用性。