Progesterone plays a critical role in embryonic and fetal development. Among its actions, progesterone can suppress many components of the immune system. This immunosuppressive effect may be an important aspect of progesterone's role as a pregnancy hormone: the fetal-placental unit is an allogeneic tissue that would be immunologically rejected by the mother without some alteration in immune responses at the maternal-fetal interface. While elevated secretion of progesterone may therefore be beneficial to the fetal allograft, the immunosuppressive actions of progesterone can also have negative consequences to promote the establishment of genital tract infections. Using the sheep as a model, recent results suggest that many effects of progesterone on uterine immunity are mediated indirectly through the induction of uterine secretory products that modulate lymphocyte function. Specifically, progesterone induces a high-molecular-weight protein in uterine secretions called megasuppressin (MS) that inhibits T lymphocyte blastogenesis in vitro. The long-term goal of the proposed research is to understand the mechanism by which progesterone alters uterine immune function and use this information to reduce embryonic mortality and to decrease the incidence of genital tract infections. Specific objectives of the current proposal include using hybridoma technology to produce monoclonal antibodies, which will then be used to purify MS. Critical biochemical properties of MS will be determined and monoclonal antibodies will be used to determine the time course of MS secretion throughout pregnancy, the estrous cycle and progesterone treatment. This will test if MS contributes to enhanced incidence of uterine infections during the luteal phase of the estrous cycle. Another major objective is to elucidate the mechanism by which MS inhibits in vitro T lymphocyte blastogenesis. Specifically, it will be tested whether MS reduces secretion of IL-1 and IL-2 and responsiveness of target cells to these interleukins. In addition, it will be determined whether MS exerts its actions by activating adenylate cyclase or by inducing suppressor cell formation. The in vitro effect of MS on other subsets of T lymphocytes, B lymphocytes and neutrophils will also be tested. Should time permit, the immunosuppressive activity of MS will be tested in vivo using end points of intrauterine skin graft rejection and systemic antibody formation in response to T cell-dependent antigen.
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