The long-range goal of this project is to understand how the polymorphism of HLA class II D-region products influences immune response and susceptibility to autoimmune disease such as rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus (IDDM). T cells recognize antigen in the context of HLA class II molecules and allelic differences in class III molecules and activate alloimmune T cells. In this project, we will use cloned T cells to define individual recognition sites on D-region products as a means for identifying structural variants that might play a role in immune response. These recognition sites also might be informative for the study of disease susceptibility. There are three components to our proposal. First, we will generate T cell clones that recognize the polymorphic sites on D-region molecules associated with the DR3 and DR4 family of haplotypes. These T cell defined epitopes will be localized to specific HLA-D loci and molecules, and eventually these recognition sites will be mapped on individual HLA-D alpha and beta chains. Second, we will determine which of these T cell defined epitopes might be associated with susceptibility to RA and IDDM. Analysis with pertinent T cell clones should yield definitive information about the role of class II immune response genes as risk factors in these diseases. Third, T cells activated in vivo will be cloned from RA patients to determine whether autoreactive T cells occur in blood or synovial tissues, whether they recognize tissue-specific antigens and whether they are specific for or restricted by any particular HLA-D determinants. These latter experiments may lead to the development of a model for understanding the nature of the immune response involved in the pathogenesis of RA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR039153-04
Application #
3159121
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-02-01
Project End
1993-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
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