Regulation of CD4+ T cell responses by a progesterone receptor

黄体酮受体调节 CD4 T 细胞反应

• 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
• 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' 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

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)：孕激素受体对炎症和适应性免疫的调节作用女性性激素，如孕酮(PG)是免疫系统的强大调节剂。高PG状态，如怀孕，与类风湿性关节炎等常见自身免疫性疾病的缓解和T辅助1型(Th1)反应的抑制有关-在PG治疗后的动物模型中总结了这些效应。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；补充PG成功地预防了早产。怀孕和对动物进行PG治疗会导致免疫球蛋白水平和免疫抗体反应的改变。使用注射前列腺素避孕药的妇女感染艾滋病毒的风险大大增加；估计有5000万妇女使用这种形式的节育措施，在艾滋病毒流行的撒哈拉以南非洲地区越来越多。然而，PG在体内的免疫调节的细胞和分子靶点很大程度上是未知的。免疫细胞至少表达两种PG受体类型：胞内PG受体(IPRs)和新近发现的膜PG受体(MPR)。天然和合成的孕激素与这两种受体的亲和力各不相同。IPRs在生殖组织中具有很好的特性，但其在体内的免疫功能仍未被研究。在这里，我们建议通过评估PG治疗前后CD4+T细胞、B细胞或树突状细胞中IPR的丢失对炎症和适应性免疫反应的影响来阐明PG免疫调节的细胞和分子靶点。在IPR+小鼠体内比较赋形剂和PG治疗将使我们能够定义PG在我们系统中的影响；比较IPR+和IPR-组将使我们能够确定哪些效果需要IPR，在哪些细胞类型中，以及在什么激素条件下它们是有效的。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，以了解影响全球健康、妇女健康、母婴医学和自身免疫的重要临床现象。