Regulation of CD4+ T cell responses by a progesterone receptor

描述（由申请人提供）：黄体酮受体对炎症和适应性免疫的调节雌性类固醇如黄体酮（Pg）是免疫系统的强大调节剂。高Pg状态（如妊娠）与常见自身免疫性疾病（如类风湿关节炎）的缓解和辅助性T型1 （Th1）反应的抑制有关——Pg治疗后的动物模型重现了这些效应。th1相关细胞因子的增加与早产有关，早产是发病率和死亡率的主要原因；Pg补充剂被成功地用于预防它。动物妊娠和Pg治疗导致免疫球蛋白水平和免疫应答改变。使用注射避孕药的妇女感染艾滋病毒的风险显著增加；估计有5000万妇女使用这种避孕方式，在艾滋病毒流行的撒哈拉以南非洲越来越多。然而，体内Pg免疫调节的细胞和分子靶点在很大程度上是未知的。免疫细胞表达至少2种Pg受体类型：细胞内Pg受体（ipr）和最近发现的膜pr （mPRs）。天然的和合成的黄体酮与这两种受体的结合具有不同的亲和力。知识产权在生殖组织中有很好的特征，但它们在体内的免疫功能仍未被探索。在这里，我们建议通过评估CD4+ T细胞、B细胞或树突状细胞中ipr的丢失如何影响Pg治疗前后的炎症和适应性免疫反应，来阐明体内Pg免疫调节的细胞和分子靶点。在iPR+小鼠中比较对照剂和Pg处理将使我们能够确定Pg在我们系统中的作用；比较iPR+组和iPR-组将使我们能够确定哪些作用需要iPR，在哪些细胞类型中，以及在何种激素条件下它们是可操作的。这些实验将阐明Pg免疫调节的细胞和分子机制，并为理解影响全球健康、妇女健康、母胎医学和自身免疫的重要临床现象提供一个框架。

DESCRIPTION (provided by applicant): Modulation of inflammation and adaptive immunity by a progesterone receptor Female sex steroids like progesterone (Pg) are powerful modulators of the immune system. High Pg states, such as pregnancy, are associated with remission of common autoimmune diseases like rheumatoid arthritis, and suppression of T helper type 1 (Th1) responses - effects recapitulated in animal models after Pg treatment. Increased Th1-related cytokines are associated with pre-term birth, a major cause of morbidity and mortality; Pg supplementation is used successfully to prevent it. Pregnancy and Pg treatment in animals leads to altered immunoglobulin levels and antibody responses to immunization. Women using injectable Pg contraception are at significantly increased risk of HIV infection; and this form of birth control is used by an estimated 50 million women, increasingly in Sub-Sahara Africa where HIV is epidemic. Nevertheless, the cellular and molecular targets of Pg immunomodulation in vivo are largely unknown. Immune cells express at least 2 Pg receptor types: intracellular Pg receptors (iPRs) and recently discovered membrane PRs (mPRs). Natural and synthetic progestins bind with variable affinities to these 2 receptors. iPRs are well characterized in reproductive tissues, but their immune functions in vivo remain unexplored. Here, we propose to clarify cellular and molecular targets of Pg immunomodulation in vivo by assessing how loss of iPRs in CD4+ T cells, B cell or dendritic cells impacts inflammation and adaptive immune responses before and after Pg treatment. Comparing vehicle- vs. Pg-treatments within iPR+ mice will allow us to define Pg's effects in our system; comparing iPR+ vs. iPR- groups will allow us to determine which effects require iPRs, and in which cell types, and under what hormonal conditions they are operational. These experiments will clarify cellular and molecular mechanisms of Pg immunomodulation and reveal a framework for understanding important clinical phenomena impacting global health, women's health, maternal-fetal medicine and autoimmunity.