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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034215-04
Application #
2673986
Study Section
Special Emphasis Panel (SRC (87))
Program Officer
Hewitt, Tyl
Project Start
1995-08-03
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Giakoumopoulos, M; Golos, T G (2013) Embryonic stem cell-derived trophoblast differentiation: a comparative review of the biology, function, and signaling mechanisms. J Endocrinol 216:R33-45
Golos, T G; Giakoumopoulos, M; Gerami-Naini, B (2013) Review: Trophoblast differentiation from human embryonic stem cells. Placenta 34 Suppl:S56-61
Golos, Thaddeus G; Bondarenko, Gennadiy I; Dambaeva, Svetlana V et al. (2010) On the role of placental Major Histocompatibility Complex and decidual leukocytes in implantation and pregnancy success using non-human primate models. Int J Dev Biol 54:431-43
Drenzek, Jessica G; Vidiguriene, Jolanta; Vidiguris, Geminis et al. (2009) Suppression of Mamu-AG by RNA interference. Am J Reprod Immunol 61:453-61
Dambaeva, Svetlana V; Breburda, Edith E; Durning, Maureen et al. (2009) Characterization of decidual leukocyte populations in cynomolgus and vervet monkeys. J Reprod Immunol 80:57-69
Bondarenko, Gennadiy I; Dambaeva, Svetlana V; Grendell, Richard L et al. (2009) Characterization of cynomolgus and vervet monkey placental MHC class I expression: diversity of the nonhuman primate AG locus. Immunogenetics 61:431-42
Dambaeva, S V; Bondarenko, G I; Grendell, R L et al. (2008) Non-classical MHC-E (Mamu-E) expression in the rhesus monkey placenta. Placenta 29:58-70
Drenzek, Jessica G; Breburda, Edith E; Burleigh, David W et al. (2008) Expression of indoleamine 2,3-dioxygenase in the rhesus monkey and common marmoset. J Reprod Immunol 78:125-33
Bondarenko, Gennadiy I; Burleigh, David W; Durning, Maureen et al. (2007) Passive immunization against the MHC class I molecule Mamu-AG disrupts rhesus placental development and endometrial responses. J Immunol 179:8042-50
Slukvin, I I; Grendell, R L; Rao, D S et al. (2006) Cloning of rhesus monkey LILRs. Tissue Antigens 67:331-7

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