Antigen and nonantigen driven TCR repertoires in arthritis

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One overall goal of this project is to delineate changes in putative antigen and non antigen driven T-cell clonal repertoire in psoriatic arthritis synovia before and after receiving potential disease modifying therapy in pilot trials. Once progress has been made towards this end parallel studies will be initiated in rheumatoid arthritis as the second overall goal. The first objective is to validate this approach of repertoire analysis to gain insight into the mechanism and efficacy of therapeutic interventions and for advancing insight into the cognitive immune recognition events driving the disorder. This project is based on the preliminary observation that the vast majority of synovial T-cells in untreated psoriatic arthritis consists of apparently non antigen driven single sequence clones, with the balance containing oligoclonally expanded, and putatively autoantigen- driven, clones of both CD4 and CD8 lineage. After methotrexate, the uninflammed synovium, in striking contrast, exhibited a profound decrease in this polyclonal component and a marked expansion of clones identical in sequence to those found as a minor feature in the active synovitis sample from the same joint. Accordingly, we hypothesize that methotrexate is an example of an agents that acts to reduce the non antigen-specific polyclonal recruitment that underlies clinical synovitis, but does not significantly affect clonal expansions of autoreactive T-cells involved in the fundamental immune recognition events driving the psoriatic arthritis. The proposed experiments exploit the potential to determine whether novel therapeutic agents affect either the putative antigen specific oligoclonal or the non antigen specific polyclonal component of synovitis, or both. The methotrexate studies will be continued along with pilot studies exploring treatment of an additional group of patients with a novel CD3 Mab that appears to anergize activated TH1 cells, the sTNFR:Fc competitive inhibitor Embrel and, potentially CD40L Mab. With the hypothesis that SDF-1 plays a significant role in the localization of a autoimmune response to the joint and its subsequent development into autoimmune disease, an envisioned future trial of a CXCR4 blocking agent is preliminary sketched as an example of a concept developed out of a fundamental gene discovery effect on the distinctive phenotype of cultured rheumatoid arthritis synoviocytes. In a second objective additional proposed studies are proposed to increase information on the nature of the surprising CD4 clonal expansions that are made more evident upon methotrexate administration and initiate an understanding of their role in psoriatic arthritis. It is hypothesized that they illustrate an instance of the "three cell interaction" involved in the generation of effector cytotoxic T lymphocytes under the influence of a cognate regulatory helper cell interacting with a dendritic cell.