The maternal recognition and immunological tolerance of pregnancy in women is incompletely understood. Because the structural and functional organization of the placenta, the physiology of pregnancy and the MHC of primates is unique, the nonhuman primate represents the most appropriate model to study this question. However, this topic remains essentially unexplored in a nonhuman primate model. We hypothesize that the expression of nonpolymorphic MHC class I molecules on the rhesus monkey placenta is important in the immunological tolerance of the fetus, and have demonstrated expression of an HLA-G-like mRNA in placental tissue and cultured trophoblasts. To develop the rhesus monkey as a model for this aspect of human pregnancy we propose the following aims: 1) To define MHC Class I expression in the rhesus monkey placenta and the lymphocytic infiltrate with a systematic histological analysis. 2) To clone, sequence, express and analyze biochemically the HLA-G homolog in the rhesus monkey. 3) To examine the ontogeny of the various rhesus MHC class I molecules in early embryonic development in vivo, with preimplantation embryos and placentas during the first 4 weeks after implantation, and in vitro, in newly developed embryonic stem cells during differentiation to trophectoderm/trophoblast progenitors. 4) To determine how rhesus monkey nonpolymorphic MHC class I gene expression may be differentially regulated by contrasting the effects of cytokines on their expression in rhesus monkey extravillous trophoblast cell lines (EVTBs) and primary syncytiotrophoblast cultures (STBs). 5) To assess the functional activity of the rhesus HLA-G homolog by eluting peptides from this molecule. The significant advantage of a nonhuman primate model is the ability for physiological experimentation. The comprehensive definition of the components of MHC class I expression in the current proposal will allow a full-scale exploration of mechanisms of embryonic/fetal-maternal tolerance in the rhesus monkey. Potential further approaches include investigating whether placental MHC class I proteins can mediate immune protection from NK cell susceptibility in vitro and in vivo, and assessing the importance of nonpolymorphic MHC class I molecules in the establishment and maintenance of pregnancy. Such investigations are not feasible with human subjects, yet are essential to understand both normal fertility, and aspects of chronic human infertility in the clinical setting.
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