SEX HORMONE REGULATION OF THE MUCOSAL IMMUNE SYSTEM

粘膜免疫系统的性激素调节

• 批准号: 2059984
• 负责人: Charles Robert Wira
• 金额: $ 23.15万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2059984
• 关键词: T lymphocyte; antigen presentation; antigen presenting cell; cytokine; estradiol; genital secretion; hormone regulation /control mechanism; immunity; immunoglobulin A; immunoglobulin G; in situ hybridization; interferons; interleukin 1; interleukin 2; laboratory rat; mucosa; progesterone; secretory immune system; sex hormones; uterus

The broad objectives of the research proposed in this application are to understand at the cellular and molecular levels, the physiological actions of sex hormones on the mucosal immune system. These actions account for changes in humoral and cellular immunity and have clinical applications in the treatment of venereal diseases, autoimmune diseases, malignancy, infertility and fertility control. Studies will be undertaken to: (1) examine the regulation by sex hormones and antigens of immune cells in the female reproductive tract; (2) elucidate the role of selected cytokines in the response of the genital tract to antigens and identify the way in which they interact with sex hormones to influence mucosal immunity; (3) identify the mechanism(s) responsible for estradiol-regulated movement of IgA and IgG; and (4) study the role of sex hormones antigens and cytokines in regulating secretory component (SC) and IgA gene expression. (1) As shown in the P.I.'s laboratory, intrauterine, Peyer's patches and intraperitoneal immunization leads to pronounced genital tract IgA- and IgG-antibody responses. These studies indicate that female sex hormones play a central role in genital tract immune responses, which vary with hormone balance, immunization site and secretion analyzed. Effects of the sex hormones on the presence and function of T- and B-lymphocytes, monocytes/macrophages and dendritic cells in the genital tract will be determined both prior to and following antigen exposure. Since uterine cells express MHC class II molecules, we will establish whether uterine immune cells process and present antigen. Sites (uterus, lymph nodes, spleen) of antigen presentation to T-lymphocytes will be identified and the role of sex hormones in the regulation of these events will be determined. (2) Since cytokines are used by immune cells for communication, we will examine the role of selected cytokines in regulating genital tract antibody responses to antigen. Possible cytokine synthesis by immune cells in the genital tract will be investigated. As a part of these studies, we will determine whether cytokine production is regulated by sex hormones and antigen. (3) Because sex hormones and selected cytokines control IgA levels in genital tract secretions, we will define the mechanism(s) whereby sex hormones, IFN-gamma and the interleukins regulate IgA movement in the uterus. Uterine epithelial cells will be grown to confluence on permeable membranes. Sex hormones and cytokine control of IgA transport will be analyzed to determine immunoglobulin specificity, directional movement and rate of transport. Since IgG is also controlled by sex hormones, we will determine whether IgG movement is receptor mediated or due to fluid phase pinocytosis. (4) Secretory component, the receptor for polymeric IgA, is the cornerstone of the efferent arm of the mucosal immune system. By regulating SC production, sex hormones, antigen and IFN-gamma exercise precise control over the presence of IgA in genital tract secretions. To study the mechanism(s) of estrogen, antigen and cytokine action, SC mRNA and IgA mRNA levels will be measured in uterine and cervico-vaginal tissues. If SC and/or IgA mRNA is hormonally regulated, then synthesis of message will be analyzed. In situ hybridization studies will be carried out to identify cells in the reproductive tract that synthesize SC and IgA.

本应用程序提出的研究的广泛目标是 在细胞和分子水平上了解生理作用 粘膜免疫系统上的性激素。 这些动作说明 体液和细胞免疫的变化，并在 治疗性病，自身免疫性疾病，恶性肿瘤， 不育和生育控制。 研究将进行：（1）检查性激素的调节 女性生殖道中免疫细胞的抗原； （2） 阐明选定的细胞因子在生殖器反应中的作用 对抗原的区域并确定与性相互作用的方式 激素影响粘膜免疫； （3）确定机制 负责IgA和IgG的雌二醇调节运动； （4）研究 性激素抗原和细胞因子在调节分泌中的作用 成分（SC）和IgA基因表达。 （1）如P.I.的实验室，宫内，Peyer的补丁和 腹膜内的免疫导致明显的生殖道Iga和 IgG抗体反应。 这些研究表明女性性激素 在生殖道免疫反应中起着核心作用，随着 激素平衡，免疫部位和分泌分析。 效果 性激素在T-和B淋巴细胞的存在和功能上， 生殖道中的单核细胞/巨噬细胞和树突状细胞将是 在抗原暴露之前和之后确定。 从子宫开始 细胞表达MHC II类分子，我们将确定子宫是否子宫 免疫细胞加工并呈现抗原。 位点（子宫，淋巴结， 将确定向T淋巴细胞的抗原表现出来的脾脏） 性激素在调节这些事件中的作用将得到确定。 （2）由于免疫细胞使用细胞因子进行通信，我们将 检查选定的细胞因子在调节生殖道抗体中的作用 对抗原的反应。 免疫细胞中可能的细胞因子合成 生殖道将研究。 作为这些研究的一部分，我们将 确定细胞因子的产生是否受性激素调节和 抗原。 （3）因为性激素和选定的细胞因子控制IgA水平 生殖道分泌物，我们将定义性别的机制 激素，IFN-gamma和白细胞介质调节IgA运动中的IgA运动 子宫。 子宫上皮细胞将在可渗透的汇合处生长 膜。 性激素和IgA转运的细胞因子控制将是 分析以确定免疫球蛋白特异性，方向运动和 运输速率。 由于IgG也受性激素控制，我们将 确定IgG运动是介导还是由于流体相介导的 皮细胞增多。 （4）分泌成分，聚合物IgA的受体，是基石 粘膜免疫系统的传出臂。 通过调节SC 生产，性激素，抗原和IFN-Gamma锻炼精确控制 在生殖道分泌物中存在IgA。 研究 雌激素，抗原和细胞因子作用，SC mRNA和IgA mRNA的机理 水平将在子宫和子宫颈阴道组织中进行测量。 如果sc 和/或IgA mRNA受到荷尔蒙调节，然后消息的综合将是 分析。 将进行原位杂交研究以识别 合成SC和IgA的生殖道中的细胞。