PROGESTERONE-INDUCED UTERINE IMMUNOREGULATORY PROTEINS

The ability of progesterone to inhibit the immune system may be an important function of this pregnancy hormone: the conceptus is an allogeneic tissue that would be immunologically rejected without alteration in maternal immune responses. The immunosuppressive actions of progesterone can also have negative consequences by promoting genital tract infections. Using the sheep as a model, many effects of progesterone on uterine immunity appear to be mediated indirectly through induction of uterine secretory products that modulate lymphocyte function. The most abundant of these is a pair of related glycoproteins of the serpin superfamily of serine protease inhibitors called the uterine milk proteins (UTM-proteins). The long-term goal of the proposed research is to understand how progesterone alters uterine immune function and use this information to limit conceptus mortality and growth reduction associated with immunologic causes and to decrease the incidence of genital tract infections. The immediate goal is to rigorously test the thesis that the UTM-proteins play an important role in mediating effects of progesterone on immune function. The approach will be to test whether the UTM-proteins can cause effects on uterine immune function previously shown to be induced by progesterone and evaluate whether UTM-proteins can alter other aspects of in vivo immune responses. For Objective 1, it will be tested whether co-administration of UTM-proteins reduces antibody formation in response to immunization to a T-dependent antigen, ovalbumin. For Objective 2, effects of UTM-proteins on delayed hypersensitivity reactions to intradermal challenge with purified protein derivative in ewes previously immunized against Mycobacterium tuberculosis will be evaluated. The ability of UTM-proteins to prolong survival of intrauterine skin grafts will be evaluated for Objective 3 and effects of UTM-proteins on lymphocyte subpopulations and antibody production in the uterine endometrium will be examined for Objective 4. For Objective 5, the mouse will be used as a model to evaluate whether treatment with UTM-proteins reduces the severity of the graft vs. host reaction, skin graft rejection response and natural-killer cell mediated abortion induced by poly (I).poly (Cl2U) administration. The objectives listed above will provide an unambiguous test of whether the UTM-proteins possess immunoregulatory properties and are critically important to test the thesis that progesterone exerts its primary inhibitory actions on uterine immunity through the production of uterine-derived and locally-acting immunosuppressive substances.