In preliminary experiments that prompted this grant application, we have shown that: i) peptides of bacterial origin (E. coli dnaJ heat shock protein) are a target of pro-inflammatory T cell responses in rheumatoid arthritis (RA) patients. dnaJ shares with HLA DRBI*0401 the susceptibility sequence to RA (shared epitope). Based upon these initial results, we have proposed dnaJ as one of the possible antigens, which may contribute to the generation of chronic autoimmune inflammation in RA; ii) T cells in the blood of RA patients that react with the shared epitope can be identified, isolated and characterized, using a novel technical approach (T cell capture: TCC), which we have developed; iii) We have identified a dnaJ-derived peptide (dnaJP1) which has been successfully tested in Phase I of a clinical trial aimed at modulating these pro-inflammatory responses in RA. This proposal is connected to a pilot Phase II, double blind, placebo controlled trial of modulation of inflammatory responses to dnaJPl in RA. We will evaluate in that study efficacy of immunomodulatory treatment by clinical and immunological outcome measurements. We will extend this analysis to study the effect of the treatment on antigen-specific T cells, in order also to identify surrogate markers for disease activity and treatment efficacy. The trial is due to start in February 2000. The above mentioned project, while providing a comprehensive analysis of immune changes induced in RA patients by an immunomodulatory treatment, still falls short in evaluating phenotypical and functional changes induced by the treatment at synovial sites of inflammation. Here, we propose to analyze such changes longitudinally in synovial biopsies samples obtained from the cohort of patients enrolled in the trial at the UCSD site. Cytokine production of the samples will be performed, and correlated with immunological and clinical data obtained from the Phase II project.
The specific aims for this project are: (1) To collect synovial biopsies from patients enrolled in the Phase II trial at baseline and end-treatment (six months duration) points; (2) to establish a library of samples suitable for molecular biology, immunology and histology studies; and (3) to extract evaluate production of pro-inflammatory and tolerogenic cytokines and chemokine receptors expression by real-time PCR (TaqMan)
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