This project will study the regulation of cytokine production and T cell activation in the rheumatoid synovial microenvironment. The overall goal of this project is to study modes and sequelae of interactions between T cells and nonlymphoid cells within rheumatoid synovium. The effect of these interactions on T cell activation, differentiation and functional status will be assessed, as well as the effect of these interactions on synovial microenvironment cell activation and cytokine production. Individual specific aims are: 1) to phenotypically and functionally characterize nonlymphoid cells within the RA synovial microenvironment using new monoclonal and polyclonal antibodies against functionally relevant or tissue specific molecules; 2) to study the phenotype and function of T cells in RA synovium and RA synovial fluid with regard to T cell maturation status, membrane T cell gene receptor type, T cell receptor gene status, and T cell functional capabilities; 3) to study cell surface molecules involved in T cell interactions with types of synovial lining cells, macrophages, dendritic cells, and endothelial cells; and 4) to determine the effects on T cells and on RA synovial microenvironment cells of T cell binding to cells in the RA synovium with regard to T cell activation and T cell functional capabilities and as well with regard to synovial cell cytokine release and activation to proliferation. The long term goal of these studies is to determine critical events at cellular and molecular levels that are involved early on in the pathogenesis of rheumatoid arthritis such that specific modes of therapy may be developed based upon these observations.
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