Rheumatoid Arthritis (RA) is characterized by the formation of the synovial pannus, laden with inflammatory cells, which is hyperplastic and aggressive. Proliferation of new blood vessels is a prominent feature of the rheumatoid pannus. We have shown that a heterogeneity of function exists among macrophages isolated and purified directly from human rheumatoid synovial tissue in terms of their angiogenic activity. Only one subpopulation of macrophages possessed the ability to induce new blood vessel growth while other subpopulations did not. We propose to determine whether this functional macrophage heterogeneity extends to other activities of rheumatoid monocyte/macrophages, such as: production of Macrophage- derived growth factor (MDGF), Lysozyme, and Mononuclear cell factor (MCF). Since, despite the functional heterogeneity of these macrophages, no commercially available monoclonal antibody distinguishes these unique macrophage subpopulations, we plan to attempt to produce monoclonal antibodies directed against rheumatoid synovial macrophage subpopulations. Balb/c mice will be inoculated with macrophages from the RA synovial subpopulations. Spleen cells will be fused with HS-1 myeloma cells and hybridoma selection and cloning will be performed. Clones producing antibodies that react specifically with individual subpopulations will be sought. To determine whether angiogenic macrophages exists only with milieu of the joint, we will examine peripheral blood monocytes, the precursors of macrophages from patients with RA. Finally, we intend to study whether the angiogenic activity of macrophages can be modulated by antirheumatic drugs including penicillamine, gold sodium thiomalate, auranofin, and dexamethasone. Together, these observations should yield valuable insights into the pathogenesis of RA and into the mechanism of action of the drugs used to combat this potentially crippling disease.
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