Rheumatoid arthritis is characterized by joint destruction that results from the interactions between invading mononuclear cell and synovial tissue cells. A monoclonal antibody produced in the applicant's laboratory has defined a novel cell surface antigen now termed CDw60. CDw60 is present on the majority of T lymphocytes found in inflammatory synovial tissue or fluid as well as in other autoimmune lesions. Monoclonal antibody directed against CDw60 potently activates T cells and T cell clones that bear this antigen, suggesting that CDw60 represents a T cell activation pathway. Within the thymus CDw60 is found on the surface of a subset of thymocytes but is also strongly expressed on a large component of the thymic epithelium. Recently, a novel CDw60+ population of synovial tissue cells has been identified, distinct from the CDw60+ T lymphocytes, in inflammatory synovium. These synovial tissue cells have a dendritic morphology but lack class II MHC antigen expression that is characteristic of previously defined synovial dendritic cells. The CDw60 epitope that has been studied contains or depends upon an alpha 2-8 linked disialic acid moiety. Although this type of carbohydrate is best described in gangliosides, and anti-CDw60 cross-reacts against the GD3 ganglioside, considerable evidence suggests that CDw60 is a novel glycoprotein. The experiments outlined in this proposal are directed at further characterizing the CDw60 antigen and activation pathway including the CDw60+ non-T cell populations in human thymus and synovial tissue. Experiments are proposed to develop long-term lines of CDw60+ cells from synovial tissue, thymic epithelium, and in vitro pannus. Surface markers of these cells will be fully characterized within thymus, synovial tissue, and in vitro pannus, and on lines generated from these sources. In view of the ability of the anti-CDw60 to activate T cells, this monoclonal antibody will also be tested for activating properties on CDw60+ non T cell populations. The capacity of CDw60+ synovial dendritic cells to provide accessory function for T cell subsets will also be determined. The effect of anti-CDw60 on the induction and formation of in vitro pannus will also be examined. Other experiments will include analysis of the CDw60 carbohydrate epitope, cDNA cloning of the CDw60 glycoprotein, and analysis of the pattern of gene activation induced by anti-CDw60. The investigator expects that the proposed studies should provide definitive information concerning the structure of CDw60, will further characterize a novel subset of cells found within human synovial tissue, will determine whether this cell type is related to a functionally important subset of human thymic epithelium, and will begin to explore the role that such cells may play in inflammatory arthritis.
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