Dr. Lotz has identified ILA, a new member of the human NGF/TNF receptor family, and showed that ILA stimulates T cell proliferation and survival. ILA (lymphocyte activation inducible gene) is also expressed by chondrocytes, but its role in the regulation of these cells is unknown. Towards the development of therapeutic interventions he has shown biologic effects of cytokines in vivo following intramuscular injection of the cytokine genes. He has prepared expression vectors and fusion proteins for the continuation of this project. Based on the preliminary work on ILA Dr. Lotz proposes the hypothesis that this receptor is involved in the regulation of normal immune responses and chondrocyte function. ILA is expressed in the synovium and cartilage from arthritic joints and is involved in the regulation of joint inflammation and cartilage degradation. The following specific aims will address this hypothesis: 1. Characterize the role of ILA/4-lBB (the mouse homologue of ILA) in the regulation of connective tissue and immune cells in vitro. ILA/Ig fusion proteins and antibodies will be used to study the role of the receptor in the regulation of lymphocytes, monocytes, and chondrocytes. 2. Determine expression of ILA/4-lBB in tissues from patients with RA or OA. Synovial tissues will be obtained from early and late stage rheumatoid arthritis patients. Cartilage obtained at autopsy from older donors is used as a source of early osteoarthritic tissue, and tissue removed during total joint replacement surgery represents advanced disease. The tissues are analyzed for ILA expression at the protein and mRNA level. 3. Study the role of the receptors in the regulation of normal immune responses in vivo and in experimentally induced arthritis. Normal immune responses in mice to human transferrin and collagen-induced arthritis will be used as models to test the effect of 4-lBB encoding plasmids, Ig fusion proteins and antibodies on immune response and cartilage degradation in vivo. These studies will pursue the two general aims of advancing our understanding of the role of cytokines and their receptors in pathogenesis and of exploring their value as targets or means of therapeutic intervention.
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