ROLE OF PEPTIDE CHEMOTACTIC FACTORS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS

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Rheumatoid arthritis (RA) is a chronic, progressive, degenerative joint disease which causes enormous morbidity and excess mortality. In RA, inappropriate activation of inflammatory mechanisms leads to joint injury. Histological assessment of RA synovium reveals prominent infiltrates of blood-derived leukocytes. These cellular mediators initiate and sustain the inflammatory response which leads to joint injury in RA. A striking and unexplained phenomenon in RA is the spatial and temporal disassociation of inflammatory cell types: neutrophils predominate in early acute lesions and in synovial fluid, whereas mononuclear cells accumulate in synovial tissue. Two recently described peptide chemotactic factors could explain this response: Neutrophil Activating Factor (NAF) and Monocyte Chemoattractant Protein-1 (MCP) are related members of a gene family of small peptides which are selectively chemotactic for their named cell type. The underlying hypothesis of this proposal is that selective leukocyte accumulation in RA joints results from local production of NAF and MCP. To test this hypothesis, both human RA synovium and a well-characterized animal model of RA will be used: ovalbumin arthritis in the rabbit knee, elicited by intra-articular administration of ovalbumin to a previously sensitized animal. The first experimental goals will be to localize the NAF and MCP protein products and mRNA by immunohistochemistry and in situ hybridization respectively in the arthritic joint, and to correlate the sites of specific cell-type accumulation with local secretion of NAF and MCP. An essential prerequisite will be to generate the cloned cDNA's, recombinant proteins, and neutralizing antibodies to NAF & MCP to perform these studies in rabbit and human tissue. These will be used to determine the expression of NAF & MCP peptide and mRNA's during the evolution of the arthritic lesion, both in human RA and in the rabbit model. In the next phase of the study, we will determine if direct injection of recombinant rabbit-NAF and MCP into the rabbit knee joint causes arthritis. In addition we will assess the potential of gene transfer techniques to induce in vivo expression of cloned NAF and MCP cDNA's in the synovium. Finally, we will assess the contributions of NAF and MCP to causing the arthritic lesion by determining whether neutralizing antibodies to NAF and MCP inhibit the development of any facet of the arthritis. Understanding of the mechanisms that regulate inflammatory cells within the RA joint could provide the foundation for the development of novel and effective therapeutic strategies.