The human fetus is well-tolerated in utero regardless of its genetic composition, an accommodation the applicant refers to as fetomaternal tolerance (FMT). The induction of FMT is thought to be the result of suppression of potential allogeneic responses in the uterus and decidua. The major immune cell type in the uterus that could mediate rejection is the natural killer (NK) cell, suggesting that this cell type must be tolerized to the developing human in utero. Decidual NK (dNK) cells express morphological characteristics consistent with an activated phenotype but nonetheless are tolerant of fetal cytotrophoblasts. The predominant model for the induction of tolerance suggests that dNK cells do not respond to cytotrophoblasts because they express the restricted polymorphism major histocompatibility antigen designated HLA-G on their surface. The applicant proposes another paradigm, in which glycoconjugate- induced tolerance in the NK cell response is responsible for inducing FMT. In this model, glycoproteins such as embryonic alpha fetoprotein (AFP) and decidual glycodelin-A use their oligosaccharides to bind the carbohydrate recognition domains of specific killer cell activation and inhibition receptors (KARs and KIRs) expressed on the surface of dNK cells. This interaction induces the expression of the activated NK cell phenotype that is highly tolerant to fetal cells expressing the appropriate glycoconjugate signals such as HLA-G. The primary goal of this study is to carry out experiments complementing preliminary studies in support of this glycoconjugate-based model.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035652-03
Application #
6387876
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Yoshinaga, Koji
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$248,145
Indirect Cost
Name
Eastern Virginia Medical School
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Norfolk
State
VA
Country
United States
Zip Code
23501
Clark, Gary F (2010) The mammalian zona pellucida: a matrix that mediates both gamete binding and immune recognition? Syst Biol Reprod Med 56:349-64
Clark, Gary F; Dell, Anne (2006) Molecular models for murine sperm-egg binding. J Biol Chem 281:13853-6
Chalabi, Sara; Panico, Maria; Sutton-Smith, Mark et al. (2006) Differential O-glycosylation of a conserved domain expressed in murine and human ZP3. Biochemistry 45:637-47
Patankar, Manish S; Jing, Yu; Morrison, Jamie C et al. (2005) Potent suppression of natural killer cell response mediated by the ovarian tumor marker CA125. Gynecol Oncol 99:704-13
Kui Wong, Nyet; Easton, Richard L; Panico, Maria et al. (2003) Characterization of the oligosaccharides associated with the human ovarian tumor marker CA125. J Biol Chem 278:28619-34
Dell, Anne; Chalabi, Sara; Easton, Richard L et al. (2003) Murine and human zona pellucida 3 derived from mouse eggs express identical O-glycans. Proc Natl Acad Sci U S A 100:15631-6
Chalabi, Sara; Easton, Richard L; Patankar, Manish S et al. (2002) The expression of free oligosaccharides in human seminal plasma. J Biol Chem 277:32562-70
Easton, R L; Patankar, M S; Clark, G F et al. (2000) Pregnancy-associated changes in the glycosylation of tamm-horsfall glycoprotein. Expression of sialyl Lewis(x) sequences on core 2 type O-glycans derived from uromodulin. J Biol Chem 275:21928-38