Two general methods have been used to study the nature of Ir gene control and the nature of the antigenic determinants on protein antigens recognized by T cells and by B-cells. The first involves the comparison of responses of congenic strains of mice, differing only in their MHC haplotype, to a given antigen molecule. The second involves the comparison of the response of a single strain of mouse to a series of naturally occurring proteins or peptides differing in one or more amino acids. The use of monoclonal antibodies and T-cell clones is beginning to provide information in these area that heretofore was unattainable. In addition, recombinant DNA techniques, including site-directed mutagenesis, are being used in certain non-immunological areas to study the structure function relationships in proteins. To date little emphasis has been placed on the structural mechanisms by which the Ir gene product mediates MHC restriction. It is the purpose of the research in this proposal to combine recombinant DNA technology, especially site-directed mutagenesis, with specific monoclonal antibody and T-cell clonal probes to study the structural basis for antigen presentation and determinant selection. The mechanism by which immune responses to natural, complex antigens is regulated requires an in depth knowledge of the nature of the sites on the antigen molecule that is recognized by cells of the immune system and their physical relationship to each other on the surface of the antigen molecule. The complex molecule used in these studies is but a model for any naturally occurring antigen such as those present on infectious organisms, tumor specific antigens, etc. Studies such as those proposed here offer a new and powerful approach to the study of an old problem. The results obtained will provide considerable insight into the mechanisms of regulation of immune responses so necessary to a full understanding of disease processes and for the manipulation of immune responses in many diseases including all forms of cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020745-03
Application #
3130556
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1984-09-30
Project End
1988-02-29
Budget Start
1986-09-01
Budget End
1988-02-29
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Benjamin, D C (1995) B-cell epitopes: fact and fiction. Adv Exp Med Biol 386:95-108
Huczko, E L; Bodnar, W M; Benjamin, D et al. (1993) Characteristics of endogenous peptides eluted from the class I MHC molecule HLA-B7 determined by mass spectrometry and computer modeling. J Immunol 151:2572-87
Sosnick, T R; Benjamin, D C; Novotny, J et al. (1992) Distances between the antigen-binding sites of three murine antibody subclasses measured using neutron and X-ray scattering. Biochemistry 31:1779-86
Benjamin, D C; Williams Jr, D C; Smith-Gill, S J et al. (1992) Long-range changes in a protein antigen due to antigen-antibody interaction. Biochemistry 31:9539-45
Benjamin, D C (1991) Molecular approaches to the study of B cell epitopes. Int Rev Immunol 7:149-64
Smith, A M; Woodward, M P; Hershey, C W et al. (1991) The antigenic surface of staphylococcal nuclease. I. Mapping epitopes by site-directed mutagenesis. J Immunol 146:1254-8
Smith, A M; Benjamin, D C (1991) The antigenic surface of staphylococcal nuclease. II. Analysis of the N-1 epitope by site-directed mutagenesis. J Immunol 146:1259-64