Regulation of CD4+ T cell responses by a progesterone receptor

黄体酮受体调节 CD4 T 细胞反应

基本信息

批准号：
8510078
负责人：
Grant Hughes
金额：
$ 26.04万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510078
关键词：
Ablation Address Affinity Africa Animal Model Animals Antibody Formation Antigen-Presenting Cells Autoimmune Diseases Autoimmunity B-Lymphocytes Binding CD4 Positive T Lymphocytes Cells Clinical Communicable Diseases Contraceptive methods Dendritic Cells Disease remission Dose Epidemic Erythrocytes Female Fetus Gonadal Steroid Hormones HIV HIV Infections Health Helper-Inducer T-Lymphocyte Hormonal Hormones Immune Immune response Immune system Immunity Immunization Immunoglobulin Class Switching Immunoglobulin Switch Recombination Immunoglobulins In Vitro Infection Inflammation Inflammatory Injectable Knockout Mice Knowledge Listeria monocytogenes Maintenance Membrane Molecular Molecular Target Morbidity - disease rate Mouse Strains Mus Phenotype Population Pregnancy Prevalence Process Progesterone Progesterone Receptors Property Receptor Gene Recycling Regulation Reproduction Rheumatoid Arthritis Risk Role Sahara Series Spleen Splenic Red Pulp Structure of germinal center of lymph node Supplementation Synthetic Progestogens System T cell response T-Cell Receptor T-Lymphocyte Term Birth Testing Tissues Transgenic Mice Transgenic Organisms Viral Tumor Antigens Woman Women&apos s Health adaptive immunity base birth control cell type cellular targeting cytokine fetal fetal medicine global health immune function immunoregulation in vivo mRNA Expression macrophage mortality novel pathogen prevent protein expression public health relevance receptor receptor expression receptor function reproductive research study response senescence sexual dimorphism steroid hormone tool

项目摘要

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.

描述（由申请人提供）：孕激素受体性类固醇（如孕酮（PG））对炎症和适应性免疫的调节是免疫系统的强大调节剂。高PG状态（例如妊娠）与常见自身免疫性疾病（如类风湿关节炎）以及PG治疗后动物模型中概括的T助手1（TH1）反应的抑制作用有关。与Th1相关的细胞因子增加与期前出生有关，这是发病率和死亡率的主要原因。 PG补充成功用于预防它。动物的妊娠和PG治疗会导致免疫球蛋白水平改变和对免疫的抗体反应。使用可注射PG避孕药的妇女有显着增加HIV感染的风险。据估计，在艾滋病毒流行病的撒哈拉以南非洲，估计有5000万妇女使用了这种出生控制形式。然而，体内PG免疫调节的细胞和分子靶标在很大程度上尚不清楚。免疫细胞至少表达2种PG受体类型：细胞内PG受体（IPR）和最近发现的膜PRS（MPRS）。天然和合成孕激素与这两个受体与可变亲和力结合。 IPR在生殖组织中的特征很好，但是它们在体内的免疫功能仍未开发。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的IPR损失如何影响PG的炎症和PG处理前的适应性免疫反应，以阐明体内PG免疫调节的细胞和分子靶标。比较IPR+小鼠中的车辆与PG处理，将使我们能够定义PG在系统中的影响；比较IPR+与IPR-组将允许我们确定哪些效果需要IPR，在哪种细胞类型中以及在哪种激素条件下它们的运行。这些实验将阐明PG免疫调节的细胞和分子机制，并揭示一个框架，以理解影响全球健康，妇女健康，孕妇医学和自身免疫性的重要临床现象。