Members of the chemokine family, such as the C-X-C chemokine, interleukin-8 (IL-8), and the C-C chemokine, monocyte chemattractant protein-1 (MCP-1), which are chemoattractants for neutrophils and monocytes, respectively, have been associated with rheumatoid arthritis. The studies outline herein will determine the contribution of members of the C-X-C, C-C, and C chemokine family members in experimental arthritis which mimics aspects of rheumatoid arthritis. Assessment of direct intraarticular exposure to the various chemokine members that are neutrophil, monocyte, and lymphocyte chemattractants, respectively, coupled with detection of the time course of chemokine expression in adjuvant arthritis in rats will determine those molecules most closely related to inflammatory cell influx in the joint. The actual phlogogenic role will be established using neutralizing antibodies specific for the chemokine in question. For clinically useful therapy, the major focus of the study will be to express receptor blockers affecting receptors common to more that one chemokine. The sharing of receptors by a member of chemokines will allow very effective inhabitation of several of these proinflammatory molecules with a minimal number of receptor blockers. Blockers for rat MCP-1 and KC have already been produced in the laboratory in active form as tested in vitro. These blockers, are effective in a renal model of immune inflammatory injury, and are available for in vivo study in experimental arthritis. These studies will be combined with the evaluation of neutralizing antibodies directed toward the receptor molecules themselves, which have already been cloned in the laboratory. The newly discovered C chemokine, lymphotaxin (Ltn), alumphocyte chemoattractant, has also been cloned and expressed in our laboratory and its receptor blocker are being sought. This chemokine has been found, in our preliminary studies, to be expressed during the early stages of arthritic involvement in the adjuvant arthritis model. The novel expression system established for production of the chemokine receptor blockers in E. coli will provide a feasible and economical way to extend these approaches to patients with rheumatoid arthritis.
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