The ultimate goal of this research program is to understand, in terms of the interactions of specific amino acids, the recognition byu cytotoxic T-lymphocytes (CTLs) of class I molecules encoded in the major histocompatibility complex of the mouse. Two complementary approaches will be used to create synthetic target structures for CTL recognition. First, a fused exon construct, which has recently been completed, will be used for cassette mutagenesis (in vitro gene conversion) to generate a family of mosaic Ld-Dd class I molecules and to investigate their recognition by Ld and Dd specific CTLs. This fused exon will also be used to introduced other class I-specific and even class II- specific sequences into the Ld molecule, in order to explore T lymphocyte reactivity. Second, class I-derived peptides, which bind to class I molecules,can be used to generate CTL epitopes, as described in the Progress Report, see page 25; we will determine the scope of this phenomenon. The projects outlined in this research program will lead to an in depth understanding of the important structural elements which MHC molecules must posses for T-lymphocyte recognition. This is a prerequisite for the successful manipulation of the immune response and should result in the development of molecularly rational therapies for many diverse disease such as cancer, autoimmune conditions as well as transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM036804-08
Application #
3291289
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1985-09-27
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Ochoa-Garay, J; McKinney, D M; Kochounian, H H et al. (1997) The ability of peptides to induce cytotoxic T cells in vitro does not strongly correlate with their affinity for the H-2Ld molecule: implications for vaccine design and immunotherapy. Mol Immunol 34:273-81
Louie, K A; Ochoa-Garay, J; Chen, P J et al. (1996) H-2Ld-alloreactive T cell hybridomas utilize diverse V alpha and V beta T cell receptor chains. Mol Immunol 33:747-58
Frelinger, J A; McMillan, M (1996) The role of peptide specificity in MHC class I-restricted allogeneic responses. Immunol Rev 154:45-58
Killion, C C; Chen, P J; Dadgari, J M et al. (1995) Dissection of cross-reactivities using a panel of H-2Ld alloreactive T cell hybridomas. Cell Immunol 164:81-9
Benichou, G; Fedoseyeva, E; Lehmann, P V et al. (1994) Limited T cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J Immunol 153:938-45
Benichou, G; Fedoseyeva, E; Olson, C A et al. (1994) Disruption of the determinant hierarchy on a self-MHC peptide: concomitant tolerance induction to the dominant determinant and priming to the cryptic self-determinant. Int Immunol 6:131-8
Fahnestock, M L; Dadgari, J M; McMillan, M et al. (1994) Phosphatidyl inositol-linked forms of a murine class I MHC molecule expressed on Chinese hamster ovary cells retain peptide binding capability and alloreactivity. Int Immunol 6:307-14
McKinney, D M; Chen, P; McMillan, M (1994) Single Dd amino acid substitutions in the H-2Ld molecule identify antibody epitopes. Immunogenetics 39:440-3
Hioe, C E; McKinney, D M; Frelinger, J A et al. (1994) Mutations inside but not outside the peptide binding cleft of the H-2 Ld molecule affect CTL recognition and binding of the nucleoprotein peptide from the lymphocytic choriomeningitis virus. Immunogenetics 40:222-9
Benichou, G; Takizawa, P A; Olson, C A et al. (1992) Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J Exp Med 175:305-8

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