It is the hypothesis of this grant application that the pathogenesis of rheumatoid arthritis (RA) depends not upon the absolute numbers of T cells in the blood or the joints, but rather upon the relative percentages of auto-antigen specific T cells that produce and respond to pro-inflammatory and anti-inflammatory signals, including cytokines and chemokines. These T cell populations may be the target for therapeutic intervention. In preliminary experiments that prompted this grant application, we have shown that: i) peptides of bacterial origin (E. coli dnaJ heat shock protein) are strong immunogens in RA patients. dnaJ shares with HLA DRB1*0401 the susceptibility sequence to RA (shared epitope); ii) T cells in the blood RA patients that react with the shared epitope can be identified and isolated, using a novel technical approach; iii) T cell receptors usage and patterns of cytokine production by these shared epitope specific T cells can be analyzed. Based upon these initial results, we now need to test our hypothesis in a larger cohort of RA patients with different disease courses, and responses to treatment. Thus, the aims of this project are: 1. To characterize frequencies, function and phenotypes of T cells in RA patients reactive with the shared epitope. Parameters to be studied will include cytokine production, T cell receptor usage and membrane markers of activation and memory. Chemokine receptors will also be studied. 2. To determine the effects of disease activity and severity, and of slow acting anti rheumatic drugs, on function and phenotype of the shared epitope specific and bystander T cells. 3. To develop methods to modulate the Th1-type phenotype of shared epitope specific T cells, using in vitro immune manipulation with altered peptides. The long term objectives of this project are: i) to contribute to a better understanding of T cell-mediated events in the pathogenesis of rheumatoid arthritis; (ii) to develop paradigms for the prediction of disease outcome, and for evaluation rapidly new models of therapy.
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