The unique expression of MHC class I molecules HLA-G and particularly HLA-C in extravillous trophoblasts is thought to be a critical element of human pregnancy. Although their MHC is rapidly evolving, it is clear that other primates have actively retained placental expression of genes orthologous or homologous to HLA-G, and the receptors for MHC class I molecules, the KIR and LILR gene family members, are undergoing parallel evolution and reflect the diversity of their cognate MHC molecules. However, a full understanding of the dialog between placental MHC class I molecules and specific receptors on decidual leukocytes in vivo, and their potential as therapeutic targets in cases of adverse pregnancy outcomes will require better development of appropriate animal models. We have extensively characterized the expression of Mamu-AG, a nonclassical MHC class I molecule with apparently restricted polymorphism expressed in rhesus monkey trophoblasts. We have formulated a new hypothesis that although the rhesus does not have an orthologous MHC-C locus, placental Mamu-AG will fulfill the placental role of human HLA-C. To test this hypothesis and move this important animal model forward, we propose three Specific Aims.
Specific Aim 1. To define the polymorphism of placental MHC class I mRNAs expressed in rhesus monkey trophoblasts by high throughput pyrosequencing.
Specific Aim 2. To define the expression of KIR and LILR mRNAs in rhesus monkey decidual and peripheral blood leukocytes using a novel pyrosequencing-based phenotyping approach.
Specific Aim 3. To express recombinant Fc-tagged rhesus decidual KIR/LILR receptors and use these as probes to identify candidate receptors for placental Mamu-AG. These studies propose to reframe our understanding of rhesus placental MHC expression, and move the field forward by defining the candidate receptors present on rhesus peripheral blood and decidual leukocytes. Defining the Mamu-AG receptor(s) on decidual leukocytes will strengthen interpretation of ongoing and future in vivo experiments with rhesus monkeys in the study of maternal immune recognition and response in implantation, early placental and decidual development, and fetal well-being and pregnancy outcome, as well as placental influences on the endometrial mucosal immunological environment.
Although it is widely held that early disruption of the immune dialog between the placental and maternal systems can be severely detrimental to pregnancy success and maternal and fetal well-being, the ways that the placenta informs the maternal immune system of pregnancy, and the specific adaptations that the local decidual immune cells make to insure pregnancy success remain poorly understood, This proposal will establish a definitive foundation of rhesus monkey placental MHC class I biology, and identify candidate receptors on maternal immune cells that define the responses to pregnancy in this important animal model of human pregnancy. The ultimate goal is to identify therapeutic approaches for devastating disorders of human pregnancy in which disrupted maternal-fetal immune regulation is strongly implicated, including recurrent pregnancy loss and spontaneous miscarriage, preeclampsia and intrauterine growth restriction, and intrauterine infection and preterm labor.
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