IMMUNOREGULATORY EFFECTS OF ESTROGEN IN EAE

雌激素对 EAE 的免疫调节作用

• 批准号: 7281673
• 负责人: Halina Offner
• 金额: $ 31.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-28 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281673
• 关键词: Accounting; Affect; Animal Model; Antibodies; B-Lymphocytes; Bone Marrow; CXC Chemokines; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Condition; Contraceptive methods; Dendritic Cells; Disease Progression; Electron Microscopy; Encephalomyelitis; Estradiol; Estrogens; Ethinyl Estradiol; Experimental Autoimmune Encephalomyelitis; Future; Genetic Polymorphism; Grant; Hematopoietic; Individual; Inflammatory; Knockout Mice; Ligands; Marines; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Basic Proteins; Oral; Pathway interactions; Patients; Peptides; Placebos; Population; Pregnancy; Prevention; Production; Proteins; Proteolipids; Refractory; Relapse; Role; Signaling Molecule; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Transcriptional Activation; Tumor Necrosis Factor-alpha; Up-Regulation; base; cell type; chemokine; cytokine; human TNF protein; human disease; immunoregulation; interest; macrophage; neurofilament; oligodendrocyte-myelin glycoprotein; prevent; programs; protective effect; receptor

DESCRIPTION (provided by applicant): Treatment with 17beta-estradiol (E2) can prevent clinical and histological signs of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). E2 inhibited activation, production of cytokines (particularly TNF-alpha) and chemokines, and encephalitogenic activity of marine T cells, and prevented recruitment of inflammatory cells into the CNS. During the past granting period, we demonstrated that mice lacking Esr1 (alpha receptor for E2) but not Esr2 (beta receptor for E2) were refractory to E2-mediated inhibition of chronic EAE, thus implicating Esr7 in E2-mediated protection. Moreover, we found that E2 treatment did not directly inhibit pathogenic T cells. Transfer of E2-conditioned Esrf+ dendritic cells (DC) into Esr1 knockout mice completely suppressed EAE, indicating that DC represent at least one critical E2- sensitive cell type. Moreover, we found that E2 could up-regulate expression of FoxP3 and potentiate the regulatory activity of CD4+CD25+ Treg cells through Esr1. Of importance, E2-conditioned DC had both reduced ARC function for activating encephalitogenic T cells, and enhanced induction of CD4+CD25+FoxP3+ Treg cells. One mechanism that could account for the protective effects of E2 is its pronounced up-regulation of the PD-1 (programmed death-1) marker on DC macrophages, B cells and T cells, a finding relevant to a recently described PD-1 polymorphism associated with MS disease progression. Although our recent results have narrowed the candidates that contribute to E2 prevention of EAE, key issues still remain, including additional critical E2-sensitive cell types and the role of PD-1 in E2-induced immunoregulation. Moreover, unlike E2 that can prevent but not treat established EAE, ethinyl estradiol (EE) used in oral contraception has therapeutic effects on EAE, raising the fundamental question of whether this structurally different molecule signals through Esr1 and activates critical E2-sensitive pathways. We here propose to test the hypothesis that E2-mediated protection and EE-mediated therapy primarily involve Esr1- dependent APC and Treg cells that affect the course of EAE through enhanced PD-1 expression, reduced APC function, and heightened activity of CD4+CD25+FoxP3+ Treg cells. We thus propose to identify E2- sensitive cell types that are crucial for Esr7-mediated protection against EAE, evaluate the role of PD-1 and its ligands in the protective mechanism, and distinguish therapeutic and neuroprotective effects of EE vs. E2 in relapsing, chronic, and spontaneous models of EAE. These studies will clearly establish E2- and EE- dependent pathways of EAE protection and therapy that may have direct relevance for future clinical trials in MS patients.

描述（由申请人提供）：用17β-雌二醇（E2）治疗可以预防实验性自身免疫性脑脊髓炎（EAE）的临床和组织学症状，EAE是多发性硬化症（MS）的动物模型。 E2 抑制海洋 T 细胞的激活、细胞因子（特别是 TNF-α）和趋化因子的产生以及致脑炎活性，并阻止炎症细胞募集到 CNS。在过去的授权期间，我们证明缺乏 Esr1（E2 的 α 受体）而不是 Esr2（E2 的 β 受体）的小鼠对 E2 介导的慢性 EAE 抑制具有抵抗力，因此暗示 Esr7 参与了 E2 介导的保护。此外，我们发现E2处理并不能直接抑制致病性T细胞。将 E2 条件 Esrf+ 树突状细胞 (DC) 转移到 Esr1 敲除小鼠中完全抑制了 EAE，表明 DC 代表至少一种关键的 E2 敏感细胞类型。 Moreover, we found that E2 could up-regulate expression of FoxP3 and potentiate the regulatory activity of CD4+CD25+ Treg cells through Esr1.重要的是，E2 条件 DC 既降低了激活致脑炎 T 细胞的 ARC 功能，又增强了 CD4+CD25+FoxP3+ Treg 细胞的诱导。可以解释 E2 保护作用的一种机制是其对 DC 巨噬细胞、B 细胞和 T 细胞上的 PD-1（程序性死亡 1）标记物的显着上调，这一发现与最近描述的与 MS 疾病进展相关的 PD-1 多态性相关。尽管我们最近的结果缩小了有助于 E2 预防 EAE 的候选者范围，但关键问题仍然存在，包括其他关键的 E2 敏感细胞类型以及 PD-1 在 E2 诱导的免疫调节中的作用。此外，与可以预防但不能治疗已确诊的 EAE 的 E2 不同，口服避孕药中使用的乙炔雌二醇 (EE) 对 EAE 具有治疗作用，这就提出了一个基本问题：这种结构不同的分子是否通过 Esr1 发出信号并激活关键的 E2 敏感途径。我们在此提出检验以下假设：E2 介导的保护和 EE 介导的治疗主要涉及 Esr1 依赖性 APC 和 Treg 细胞，它们通过增强 PD-1 表达、降低 APC 功能和增强 CD4+CD25+FoxP3+ Treg 细胞的活性来影响 EAE 的病程。因此，我们建议鉴定对 Esr7 介导的 EAE 保护至关重要的 E2 敏感细胞类型，评估 PD-1 及其配体在保护机制中的作用，并区分 EE 与 E2 在 EAE 复发、慢性和自发模型中的治疗和神经保护作用。这些研究将明确建立 EAE 保护和治疗的 E2 和 EE 依赖性途径，这可能与未来多发性硬化症患者的临床试验直接相关。