The tissues of the human female reproductive tract (FRT) exhibit defined and organized microenvironments that influence immune cell function. Furthermore, the sex steroid hormones, estradiol and progesterone, have a controlling influence on both the afferent and the efferent arms of the immune system. To date, studies of the human mucosal immune system have largely relied on the study of isolated cells, an approach which does not allow evaluation of the influence of tissue architecture and microenvironment. Moreover, relatively few studies of the immune system of the human FRT have been carried out. Thus, our current understanding of the organization and function of the immune system in this critically important organ system is clearly inadequate, as is our understanding of the endocrine influences on immunity in these tissues. The proposed studies will use novel in situ techniques, which utilize viable tissue sections, to test the hypothesis that sex hormones regulate immune cell organization and function in the different microenvironments of the uterine endometrium (EM) of the FRT. In particular, we postulate that during the menstrual cycle, sex hormones and cytokines act in concern to regulate the organization and function of immune cells within the EM of the FRT. More specifically, we will: 1) Determine the organization of T and B lymphocytes and myeloid cells within the different microenvironments of the EM of the FRT and how this varies with stage of the menstrual cycle. 2) Identify the mechanisms responsible for the regulation of architectural remodeling in the EM with regard to the role of cell proliferation, apoptosis, cytokines and adhesion molecules. 3) Determine the role of sex hormones and cytokines on cytotoxic T cell and myeloid cell function in the different microenvironments of the EM. The results of these studies should provide valuable insights into the organization and function of the immune system of the FRT, which in turn will enhance our understanding of the susceptibility of the FRT to sexually transmitted diseases, and be of value in the rational design of regimens for immunization against these diseases. These studies will also contribute important information useful for the evaluation of the mechanisms leading to gynecological malignancies and other diseases of the FRT, including endometriosis.
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