The overall objective of this research proposal is to define the role of epithelial cells in the regulation of mucosal immunity in the human female reproductive tract. Epithelial cells at mucosal surfaces play major roles in immune protection including antigen recognition and presentation, cytokine synthesis, expression of adhesion molecules, and the movement of antibodies from tissue into secretions. These actions account for changes in cellular and humoral immunity and have clinical implications in the treatment of venereal diseases including HIV-1 (and causative agent of AIDS), autoimmune diseases, malignancy, and infertility. Our hypothesis is that sex hormones and cytokines regulate epithelial cells in the Fallopian tube, uterus, cervix and vagina of women at the physiological, cellular and molecular level, to either enhance and/or suppress mucosal immune responsiveness. Studies will be undertaken to: (1) Examine IgA and IgG movement through reproductive tract epithelial cells and the possible influence of sex hormones and cytokines. As shown by the PI's laboratory, IgA, IgG and secretory component (SC), the IgA receptor, are regulated by sex hormones and cytokines. The proposed studies will characterize the transport of IgA by SC through reproductive tract epithelial cells. We will also determine whether IgG movement is receptor-mediated and establish the role of sex hormones and cytokines on this movement. (2) Elucidate the regulation of HLA class I, class II, and CD4 expression on epithelial cells, and the role of sex hormones and cytokines in antigen processing and presentation by epithelial and stromal cells in the rat uterus. Our objectives in these studies will be to define their roles in the regulation of HLA class I, class II and CD4 expression and in antigen processing and presentation by human reproductive tract epithelial cells. (3) Analyze the expression and regulation of adhesion molecules in the female reproductive tract. Since adhesion molecules mediate immune cell migration, sites in the reproductive tract at which adhesion molecules (integrins, vascular addressins, and selectins) are expressed will be identified. As a part of these studies, we will define the role of these molecules in interactions of immune cells with epithelial and vascular cells, and establish whether sex hormones and cytokines control adhesion molecule expression in the reproduction tract. (4) Study the distribution of cytokine receptors and receptor mRNAs in the Fallopian tube, uterus, cervix and vagina, and role of endocrine state on their expression. To characterize the interrelationships between endocrine balance and cytokines, studies will be undertaken to measure expression of cytokine receptors, to identify which cells in the female reproductive tract express these receptors, and to define the role(s) of steroid hormones in regulating cytokine receptor and receptor mRNA levels.
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