The immunological response to placental MHC class I expression is considered to be important, yet neither the mechanisms nor the significance of this response in humans or nonhuman primates is well understood. We have recently shown that in pregnant rhesus monkeys passively immunized against Mamu-AG, the rhesus nonclassical trophoblast MHC class I molecule thought to be a homolog of HLA-G, there is a broad developmental delay in villous growth and vascularization of the placenta, a disruption of the modification of maternal decidual vessels by invasive extravillous trophoblasts, and altered decidual leukocyte responses to implantation. Hypothesizing that maternal NK cells are critical in the recognition of placental MHC, we now have pilot data demonstrating that NK cell immunodepletion has a negative impact on pregnancy outcome, causing spontaneous abortion within a week after anti-CD16 or anti-CD8 treatment. We propose that this is evidence for an important role of placental MHC class I molecules in the maternal immunological response to pregnancy in primates, and will further study the mechanisms and significance of these responses with two specific aims:

Public Health Relevance

TO PUBLIC HEALTH: Placental-maternal immune interactions are hypothesized to contribute to pathological conditions in pregnancy, ranging from infertility and spontaneous miscarriage to preeclampsia. Understanding the importance of these interactions in pregnancy success may guide preclinical studies in potential therapeutic applications of placental MHC molecules, or address the importance of deficiencies or imbalances of endometrial leukocytes in infertility or pregnancy disorders. The nonhuman primate provides a model in which pregnancy is amenable to experimental manipulation. A better understanding of the immune response to the establishment of pregnancy may have significance for understanding spontaneous miscarriage, developing therapies for threatened pregnancies, graft acceptance, and cancer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD037120-06A2
Application #
7577786
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Yoshinaga, Koji
Project Start
2009-08-15
Project End
2011-06-30
Budget Start
2009-08-15
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$574,102
Indirect Cost
Name
University of Wisconsin Madison
Department
Biology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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

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