During normal pregnancy, a semiallogeneic fetus is not rejected by the maternal immune system. The unique pattern of class I major histocompatibility complex (MHC) antigen expression seen at the human maternal/fetal interface is thought to be vital for proper fetal immune status. The lack of polymorphic class I and II MHC antigens on trophoblasts the only fetal tissue in direct contact with the mother, is likely to be at least a part of the explanation of fetal evasion of allograft rejection. The observation that the HLA-G-encoded class I MHC molecule is present on certain subpopulations of cytotrophoblasts suggests this nonpolymorphic molecule may have a role in the maternal/fetal immune response and, possibly, have a role in maintaining the immunoprivileged status of the fetus. In this request for continued support, we propose to examine the regulation and immunological role of class I MHC gene expression at the maternal/fetal interface using transgenic mice. Transgenic mice carrying a genomic fragment from the HLA-G locus express the HLA-G gene in their extraembryonic tissue in a pattern similar to the extraembryonic expression of HLA-G during human gestation. This transgenic model system will be used to delineate the cis-acting DNA elements required for proper spatial and temporal (developmental) expression of HLA-G in extraembryonic tissue. In addition, transgenic mice will be used to assess the recognition of HLA-G by T cells and whether HLA-G transgenic mice are tolerant to HLA-G. If tolerance to HLA-G is demonstrated, we will determine the role of the thymus in the induction of this tolerance. We also propose to examine the effect of extraembryonic expression of HLA-G on the maternal decidual T cell population. Finally, the role of HLA-G expressed at the maternal/fetal interface in presenting foreign antigen to the maternal immune system will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI018124-17
Application #
2671725
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1989-09-30
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
17
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Schmidt, C M; Garrett, E; Orr, H T (1997) Cytotoxic T lymphocyte recognition of HLA-G in mice. Hum Immunol 55:127-39
Schmidt, C M; Orr, H T (1995) HLA-G transgenic mice: a model for studying expression and function at the maternal/fetal interface. Immunol Rev 147:53-65
Schmidt, C M; Chen, H L; Chiu, I et al. (1995) Temporal and spatial expression of HLA-G messenger RNA in extraembryonic tissues of transgenic mice. J Immunol 155:619-29
Yelavarthi, K K; Schmidt, C M; Ehlenfeldt, R G et al. (1993) Cellular distribution of HLA-G mRNA in transgenic mouse placentas. J Immunol 151:3638-45
Schmidt, C M; Orr, H T (1991) A physical linkage map of HLA-A, -G, -7.5p, and -F. Hum Immunol 31:180-5
Killeen, A A; Sane, K S; Orr, H T (1991) Molecular and endocrine characterization of a mutation involving a recombination between the steroid 21-hydroxylase functional gene and pseudogene. J Steroid Biochem Mol Biol 38:677-86
Wei, X H; Orr, H T (1990) Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Hum Immunol 29:131-42
Koller, B H; Geraghty, D E; DeMars, R et al. (1989) Chromosomal organization of the human major histocompatibility complex class I gene family. J Exp Med 169:469-80
Mizuno, S; Trapani, J A; Koller, B H et al. (1988) Isolation and nucleotide sequence of a cDNA clone encoding a novel HLA class I gene. J Immunol 140:4024-30
Shimizu, Y; Geraghty, D E; Koller, B H et al. (1988) Transfer and expression of three cloned human non-HLA-A,B,C class I major histocompatibility complex genes in mutant lymphoblastoid cells. Proc Natl Acad Sci U S A 85:227-31

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