Immunomodulation by Pregnancy Specific Glycoprotein 17

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The mechanisms responsible for the protection of the fetal semiallograft from attack by the matemal immune system are complex and remain incompletely understood. Establishemnt of a type-2 (TH2) immune response is believed to be one 'of the key factors responsible for pregnancy success as well as for the decreases in disease activity in pregnant women suffering from certain autoimmune diseases. Hormones and eytokines produced by the placenta have been implicated in the generation of the TH2 environment. Pregnancy specific glycoproteins (PSGs) are produced by the placenta and are secreted into the maternal circulation from the time of implantation. Neutralization of PSGs by Abs leads to spontaneous abortion and PSGs induce the secretion of anti-inflammatory cytokines.These findings suggest that PSGs may have an important role in regulation of the immune response during pregnancy. Our long-term goal is to define the roles and mechanisms of action of PSGs in normal and abnormal pregnancies. The central hypothesis of this application is that murine PSG 17 contributes to the establishment of an immune environment favoring a TH2 immune response. The rationale behind the proposed research is that a better understanding of the role of PSGs in controlling immunity during pregnancy could result in the implementation of new therapies for women suffering of recurrent pregnancy losses and other immune-based pathologies. To accomplish the objectives of this applieationwe will pursue three specific aims: (1) Determine whether PSG17-CD9 interactions provide a co-stimulatory signal that stimulates naive CD4 T cell differentiation to CD4 effector T helper cells. This will be accomplished by establishing whether binding of PSG17 to its receptor CD9 affects the proliferation of these cells and the cytokines they secrete. (2) Determine whether PSG17 binding to APC favors TH2 cell development before and after Ag encounter. For this purpose, we will evaluate the effects of P SG 17 treatment of dendritic cells and the effects of P SG 17 treatment in APC in their ability to induce differentiation of T cells derived from TcR transgenic mice upon primary and secondary stimulaton. (3) Determine the nature of the in vivo response of non-pregnant PSG17-expressing mice to a parasite. Mice injected with PSG17 will be challenged with Trichuris muris and the cytokine expression in mesenteric lymph nodes, total serum Ig levels and worm burden will be analyzed.