This Research Project will define the lymphocyte populations that are present in the human uterus, Fallopian tubes, cervix, and vagina with regard to both their cell surface phenotype and function. By parallel examination of autologous lymphocytes derived from peripheral blood, differences unique to lymphoid cells resident in these reproductive tract tissues will be defined. The phenotypic and functional data obtained will be correlated retrospectively to patient history information, including most notably the influence of menstrual cycle, menopause, and hormones such as oral contraceptives, estrogens, and GnRH agonists. Based on associations that may thus be identified between lymphocyte phenotype and/or functional capabilities versus hormonal status, additional in vitro experimentation will be done in which sex hormones and cytokines will be directly tested for their effects on lymphocyte parameters. In this way, confirmation of the hormonal/cytokine regulation of lymphocyte-mediated immunity will be sought. To attain these overall goals, five Specific Aims have been formulated. First, lymphocyte subsets and heterogeneity in human reproductive tract tissues will be defined by multi-parameter flow cytometric analysis. Second, CD4+ T helper cell (Th) population will be focused on with respect to lymphokine production, ability of activated Th to induce polyclonal B cell activation, entry into cell cycle, and induction of terminal B cell differentiation resulting in production of various immunoglobulin isotypes, particularly IgA. In the third Specific Aim CD8+T cells will be examined for the presence of unique subsets relative to their peripheral blood derived counterparts and for both lytic and lymphokine producing capabilities. Both polyclonal, antigen non-specific and antigen specific lytic function will be assessed. This analysis will be extended to cytolytic T lymphocyte recognition of not only lymphoid cells, but also epithelial cells. Fourth, B cell subsets present in the reproductive tissues will be defined and compared to B cells from peripheral blood. The ability of these cells to grow, differentiate, and present antigen to CD4+ Th will be assessed. Lastly, the effects of cytokines and sex hormones on the function of T helper cells, cytolytic T lymphocytes, and B cells will be addressed as mentioned above.
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