The overall objective of this multidisciplinary Program Project is to characterize the mucosal immune system in the Fallopian tube, uterus, cervix and vagina in the human. Our hypothesis is that the reproductive tract is fully immunocompetent and that sex hormones and cytokines regulate cellular and humoral immune responses at the physiological, cellular and molecular levels. Our goal will be to define the mechanisms through which hormones and cytokines control the recognition and response arms of the immune system in the reproductive tract. Support for 3 research projects will be provided by 3 cores: Administrative, Tissue and Cell Biology. This Program Project brings together excellent scientists trained in Endocrinology and Immunology to characterize immune functions in the reproductive tract and to define the roles of steroid hormones and cytokines in mucosal immune regulation. Projects will focus on the influence of the menstrual cycle, menopause, and hormones such as oral contraceptives and estrogens, on the presence and function of immune cells in reproductive tract tissues from women undergoing hysterectomy. Interactions of steroid hormones and cytokines in regulating epithelial cell, myeloid cell and lymphocyte functions will be defined to obtain an integrated understanding of endocrine and cytokine control of mucosal immune function. Project 1 will define the central immune role of epithelial cells from the Fallopian tube, uterus, cervix and vagina in antigen processing and presentation and in the movement of IgA and IgG from tissue to lumen. In parallel studies, interactions with cytokines and the expression of adhesion molecules which influence immune cell migration into the reproductive tract will be examined. Project 2 will examine the heterogeneity of T and B cell populations in the reproductive tract and how cell distribution is altered by the menstrual cycle. Studies will investigate the impact of cytokines and hormones on the ability of helper T cells to produce lymphokines and induce immunoglobulin isotype switching, the ability of cytotoxic T cells to mediate target cell lysis, and the capability of B cells to process and present antigen and to produce antibodies of defined isotype and specificity. Project 3 will define the unique phenotypic and functional characteristics of myeloid cells in the female reproductive tract and examine the influence of cytokines and sex hormones on these characteristics. The potential of these cells to mediate cytotoxicity, to release cytokines, to respond to chemotactic stimuli, and to present antigen for initiation of specific immune responses will be determined. These studies will increase our presently limited understanding of immune protection of the female reproductive tract and should provide the basis of knowledge essential for the prevention of local infection in the genital mucosa, the management of sexually transmitted diseases, which can have devastating and irreversible effects on mother and child, and insight into the heterosexual transmission of HIV-1.
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