In the current pathogenetic model of rheumatoid arthritis (RA), chronic synovitis is understood as the result of continuous immune stimulation by persistent arthritogenic antigen in the synovium. Alternatively, the chronicity of the synovial inflammation could be related to a deficiency of anti-inflammatory, tissue protective mechanisms. Support for this alternate hypothesis comes from preliminary data demonstrating that tissue-infiltrating CD8 T cells, when tested in adoptive transfer protocols, inhibit human synovitis in vivo. In this application the role of synovial CD8 T cells as natural, yet insufficient, anti-inflammatory cells is investigated. Based on our data, we hypothesize that the activation of CD8 T cells in the tissue is antigen-driven and that the CD8 T cell-derived lymphokine, IL-16, accounts in part for the biological activity of CD8 T cells. The ultimate goal of the proposed studies is to mechanistically understand how CD8 T cells downregulate synovitis and to utilize these pathways therapeutically to suppress rheumatoid synovitis. The proposed experiments will use micromanipulation to directly isolate and molecularly characterize CD8 T cells from synovial tissue and a new """"""""animal model"""""""" created by implanting inflamed human synovium into NOD-SCID mice for in vivo functional studies. The first hypothesis proposes that antigenic peptides recognized by CD8 T cells in the tissue can be used to boost beneficial CD8 T cell responses. Relevant antigens will be identified through the use of cloned synovial CD8 T cells reacting to proteins derived from a synovium-specific expression library that has been co- transfected into COS-7 T cells with the appropriate HLA molecule. The therapeutic potential of peptide antigens will be subsequently tested in reconstituted RA synovium-SCID mouse chimeras treated with peptide vaccines. The second hypothesis states that soluble products of synovial CD8 T cells, in particular IL-16, are sufficient to mediate the anti-inflammatory action. Mechanisms regulating in situ IL-16 release will be explored and the relationship of IL-16 to other, potentially anti-inflammatory cytokines will be investigated. Lastly, we will prospectively study the representation and functional activity of tissue-infiltrating CD8 T cells in a well characterized cohort of patients with early seropositive RA. We anticipate that these studies will lead to increased understanding of the function and the anti-inflammatory potency of synovial CD8 T cells and the development of novel therapeutic approaches for patients with RA.
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