IMMUNOREGULATORY EFFECTS OF ESTROGEN IN EAE

雌激素对 EAE 的免疫调节作用

• 批准号: 7141838
• 负责人: Halina Offner
• 金额: $ 31.51万
• 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/7141838
• 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): 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17beta-雌二醇（E2）治疗可以防止实验自身免疫性脑脊髓炎（EAE）的临床和组织学迹象，这是多发性硬化症（MS）的动物模型。 E2抑制活化，细胞因子（尤其是TNF-α）和趋化因子的产生，以及海洋T细胞的脑生成活性，并防止炎性细胞募集到中枢神经系统中。在过去的给予期间，我们证明了缺乏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的抑制难治性，因此在E2介导的保护中暗示了ESR7。此外，我们发现E2处理并未直接抑制致病性T细胞。 E2条件的ESRF+树突状细胞（DC）转移到ESR1敲除小鼠中完全抑制了EAE，这表明DC至少代表一种至少一种临界E2-敏感细胞类型。此外，我们发现E2可以上调FOXP3的表达，并通过ESR1增强CD4+ CD25+ Treg细胞的调节活性。重要的是，E2条件的DC既降低了激活脑源性T细胞的弧函数，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它在DC巨噬细胞，B细胞和T细胞上对PD-1（编程死亡-1）标记的明显上调，这一发现与最近描述的与MS疾病进展相关的PD-1多态性有关。尽管我们最近的结果范围缩小了有助于E2预防EAE的候选者，但仍然存在关键问题，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建立的EAE的E2不同，用于口服避孕的乙醇雌二醇（EE）对EAE具有治疗作用，从而提出了通过ESR1结构上不同的分子信号并激活关键E2敏感途径的基本问题。我们在这里建议测试以下假设：E2介导的保护和EE介导的疗法主要涉及ESR1依赖的APC和Treg细胞，这些APC和Treg细胞通过增强的PD-1表达，APC功能降低以及CD4+CD25+CD25+FOXP3+Treg细胞的活性增强而影响EAE的过程。因此，我们建议鉴定E2敏感细胞类型，这些细胞类型对于ESR7介导的对EAE的保护至关重要，评估PD-1及其配体在保护机制中的作用，并区分EE VS. E2在复发，慢性和EAE自发模型中的治疗和神经保护作用。这些研究将清楚地建立E2和EE依赖于EAE保护和治疗的途径，这些途径可能与MS患者的未来临床试验有直接相关。