This research continues our long-term interest in the central problem of reproductive immunology and genetics: how the semiallogeneic fetus avoids rejection.
The specific aims are: First, the Pa, 213 and A/a antigens will be localized on the placenta. The morphological approach will utilize staining with the biotinylated Fab fragments of the respective antibodies and cold antibody inhibition studies to demonstrate specificity. In vivo placental immunoabsorption will be studied using radiolabeled antibodies. Cells labeled intrinsically with radioactive amino acids will be labeled extrinsically with iodine to identify the antigens that are made in the cell but not expressed on its surface and those that are expressed. Second, the structure of the class I antigens Pa, 213, A/a and F/a isolated from trophoblast cells and from lymphocytes will be compared by SDS- PAGE, isoelectric focusing, sequential immunoprecipitation, peptide mapping and carbohydrate analysis. Third, the genetic control of the expression of antigen 213 will be studied in the appropriate crosses among inbred and congenic strains. Finally, a molecular analysis of the Pa, 213 and A/a antigens in the placenta will be undertaken. The mRNA will be isolated from the placenta, and cDNA will be prepared in a lambda expression vector. The clones will be screened with murine class I probes, the appropriate cDNA will be isolated, mapped and subcloned into stable plasmids. These subclones will be sequenced and their products characterized by Western blotting. They will then be used for quantitative assessment of the three antigen transcripts in the placenta. Investigation of why the fetal allograft is not rejected will provide insight into the immunogenetics of an apparently anomalous transplantation situation and into the pathogenesis of chronic spontaneous abortion and developmental anomalies. It may also provide insight into the mechanism by which tumors avoid host immunosurveillance. This information could be used to design radically new methods of suppressing organ allograft rejection and of enhancing tumor rejection.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD009880-13
Application #
3311180
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1976-06-30
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
13
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Helou, K; Yan, Q; Yuan, X J et al. (1999) Cytogenetic localization of the growth and reproduction complex (Grc) in the rat and in the mouse and its position in relation to RT1.EC and other loci in the rat MHC. Hereditas 130:105-9
Yuan, X J; Kunz, H W; Gill 3rd, T J (1999) Physical mapping and sequencing of class I genes in a 150-kb contig in the EC region. Transplant Proc 31:1507-12
Gill 3rd, T J (1999) Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction. Am J Reprod Immunol 41:23-33
Yuan, X J; Salgar, S; McCarthy, B D et al. (1999) Molecular and biological properties of genes in the Grc and EC regions. Transplant Proc 31:1505-6
Salgar, S K; Kunz, H W; Gill 3rd, T J (1998) Structural organization, sequence analysis, and physical mapping of the Grc-linked class Ib gene RT1.S3 in the rat. Immunogenetics 48:76-81
Gill 3rd, T J (1997) Genetics of reproduction and its evolutionary significance. Am J Reprod Immunol 38:141-5
Gill 3rd, T J (1997) Genetic factors in reproduction and their evolutionary significance. Am J Reprod Immunol 37:7-16
Salgar, S K; Yuan, X; Kunz, H W et al. (1997) Physical mapping and structural analysis of new gene families RT1.S and Rps2r in the grc region of the rat major histocompatibility complex. Immunogenetics 45:353-64
Kunz, H W; Yuan, X J; Salgar, S K et al. (1997) Immunogenetic and oncogenic properties of rat trophoblast cell lines. Am J Reprod Immunol 38:158-61
Gill 3rd, T J; Salgar, S K; Yuan, X J et al. (1997) Current status of the genetic and physical maps of the major histocompatibility complex in the rat. Transplant Proc 29:1657-9

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