IMMUNOREGULATORY EFFECTS OF ESTROGEN IN EAE

雌激素对 EAE 的免疫调节作用

• 批准号: 6487971
• 负责人: Halina Offner
• 金额: $ 24.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6487971
• 关键词: T lymphocyte; clinical research; dendritic cells; estrogen receptors; estrogens; experimental allergic encephalomyelitis; female; functional /structural genomics; genetic transcription; genetically modified animals; hormone regulation /control mechanism; human subject; immunoregulation; laboratory mouse; leukocyte activation /transformation; macrophage; microarray technology; molecular pathology; multiple sclerosis; natural killer cells; protein biosynthesis; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): In patients with multiple sclerosis (MS), there is a distinct gender bias, with approximately twice as many affected females as males. Sex hormones may contribute to susceptibility or resistance to MS by influencing development and function of potentially pathogenic T cells specific for central nervous system (CNS) antigens, as well as regulatory T cells that might modify the course of disease. Previously, we reported that low doses of 17beta-estradiol (E2) can reduce severity of EAE by inhibiting activation, cytokine and chemokine production, and encephalitogenicity of murine T cells specific for myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin basic protein (MBP), and by inhibiting I recruitment of inflammatory cells into the CNS. Of particular importance, estrogen treatment profoundly reduced intracellular production of TNF-alpha, known as a critical inflammatory cytokine in EAE and MS. Recent evaluation of E2 effects on EAE using microarray analysis of splenocyte gene expression confirmed potent inhibition of TNF-alpha, and further identified several previously unsuspected immune-associated candidate genes appearing to be strongly affected by E2 treatment in vivo. These modulatory effects of estrogen on pathogenic, recruited, and regulatory cells in EAE are likely mediated y direct interaction with estrogen receptors (ER), which include the classical ER-alpha and ER-beta that are internal f receptors (iER), and possibly membrane ERs (mER) that may be distinct from iERs. This proposal will test the hypothesis that modulation of EAE by estrogen involves receptor-mediated regulation of TNF-alpha and several other novel immunerelated genes, thereby inhibiting inflammatory effects of macrophages, dendritic cells and T cells and enhancing regulatory NKT cell activity. Our primary goals are to determine if the inhibitory effects of E2 on EAE can be observed in spontaneous EAE in the absence of regulatory T and NKT cells, and if inhibitory effects of E2 on EAE are mediated through iER-alpha and /or iERbeta, or in contrast, by neither of the classical iERs. Using newly developed ER-alpha and ER-beta knockout mice we will for the first time associate E2- dependent regulation with either or both iERs, or alternatively with mER if E2 effects persist in double KO mice. Moreover, for each novel E2-affected gene implicated from the microarray analysis, we will investigate the cellular source, effects of E2 on transcription and protein production, and contribution to EAE induction in vivo. Genes found to be important in EAE will be further evaluated in blood cells from women with different levels of E2. The work proposed will identify key estrogen-sensitive genes, including TNFalpha, contributing to EAE induction and resistance. Changes in these genes can be followed during estrogen treatment as surrogate markers to verify effective doses of estrogen. From this research, we will develop a solid basis for using estrogen replacement therapy for MS.

描述（由申请人提供）：在多发性硬化症患者中 （MS），有一个明显的性别偏见，大约两倍 受影响的女性作为男性。性激素可能有助于敏感性或 通过影响潜在的发展和功能来抵抗MS 针对中枢神经系统（CNS）抗原的病原T细胞以及 作为可能改变疾病进程的调节性T细胞。以前，我们 据报道，低剂量的17beta-雌二醇（E2）可以通过 抑制激活，细胞因子和趋化因子产生，以及 特异于髓磷脂少突胶质细胞的鼠T细胞的脑生成性 糖蛋白（MOG），蛋白质蛋白（PLP）或髓磷脂碱性蛋白（MBP）， 并通过抑制I将炎症细胞募集到中枢神经系统中。的 特别重要的是，雌激素治疗大大降低了细胞内 TNF-α的产生，被称为EAE和 多发性硬化症。使用微阵列分析对E2对E2效应的评估 脾细胞基因表达证实了对TNF-α的有效抑制作用，并且 进一步识别了几个先前未经引起的免疫相关候选者 基因似乎在体内受到E2治疗的强烈影响。这些 雌激素对致病性，招募和调节细胞的调节作用 在EAE中，可能是介导的Y直接相互作用与雌激素受体（ER）， 其中包括内部F受体的经典ER-Alpha和Er-Beta （ier），可能与IER不同的膜（MER）。这 提案将检验以下假设：雌激素对EAE的调节涉及 受体介导的TNF-α和其他几种新型免疫相关的调节 基因，从而抑制巨噬细胞的炎症作用， 树突状细胞和T细胞，并增强调节性NKT细胞活性。我们的 主要目标是确定E2对E2的抑制作用是否可以 在没有调节性T和NKT细胞的情况下，在自发的EAE中观察到 如果E2对EAE的抑制作用是通过IER-ALPHA和 /或IERBETA介导的，则 或相比之下，由两个古典iers。使用新开发 ER-Alpha和Er-Beta敲除小鼠，我们将首次助理E2-- 依赖于任何一个或两个IER的调节 效果持续在双KO小鼠中。此外，对于每个新型E2影响的基因 与微阵列分析有关，我们将研究细胞 来源，E2对转录和蛋白质产生的影响，以及 对体内EAE诱导的贡献。发现基因在EAE中很重要 将进一步评估来自不同水平的女性的血细胞 E2。 提出的工作将确定关键的雌激素敏感基因，包括 tnfalpha，导致EAE诱导和抗性。这些基因的变化 可以在雌激素治疗中作为替代标记以验证 有效剂量的雌激素。从这项研究中，我们将发展一个扎实的 将雌激素替代疗法用于MS的基础。