Synovial inflammation and joint destruction in rheumatoid arthritis are complex processes, involving activation of infiltrating leukocytes and of resident synovial tissue cells. The applicant's research program has focused on the study of T cell surface structures and activation pathways that may be relevant to chronic T cell mediated autoimmune diseases, particularly rheumatoid arthritis. These studies have used a series of novel monoclonal antibodies generated in the applicant's laboratory that have identified new T lymphocyte surface structures such as CD60, and new or functionally interesting epitopes of known structures such as CD6, CD2 and CD98. CD60 is now known to be expressed on selected populations which interact with T cells in autoimmune lesions, such as RA synovium, as well as on the major T cell subset that infiltrates such lesions. The role of cell-cell interactions in inflamed synovium and of the specific surface receptors that mediate such interactions is coming into clearer focus. The applicant has recently shown that cultured type B fibroblastic synoviocytes can function as potent accessory cells for T cell responses to superantigen and lectin. Experiments are proposed for the third funding cycle (years 10-14), that would further probe the functional consequences and molecular basis for this synoviocyte - T cell interaction. Such experiments will delineate the adhesive and co-stimulatory structures important in this system, and measure cytokine gene activation in both synoviocytes and T cells. The possible role of IL-10 in shaping the pattern of the T cell response will be studied, and the levels of IL-10 in RA synovium in vivo will be measured. Other experiments will investigate the functional profile of CD60+ T cells and synoviocytes in RA. It is proposed that CD60 is a unique and valuable functional T cell subset marker. The possibility that expression of CD60 is also associated with differential susceptibility to apoptosis will be examined. Finally, a novel system which uses RA synovial engraftment in SCID mice will be employed to determine whether CD60+ T cells are preferentially selected for accumulation in synovial tissue when T lymphocytes are introduced into such animals in an extrasynovial location. The proposed experiments should shed light on the role of specific cell-cell interactions and cell surface molecules in the pathogenesis of RA and other autoimmune diseases.
Showing the most recent 10 out of 21 publications
