OBJECTIVE: To verify the hypothesis that in rheumatoid arthritis (RA), tumor necrosis factor alpha (TNFalpha) plays a critical role in regulating leukocyte trafficking and chemokine levels. METHODS: Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNFalpha monoclonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3+ T cells, CD22+ B cells, and CD68+ macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, Groalpha, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Anti-TNFalpha therapy in RA significantly reduced 111In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3+ T cells, CD22+ B cells, and CD68+ macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. CONCLUSION: TNFalpha blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.
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Aged, Antibodies, Monoclonal, Antigens, CD, Antigens, Differentiation, B-Lymphocyte, Arthritis, Rheumatoid, B-Lymphocytes, CD3 Complex, Cell Adhesion Molecules, Cell Movement, Chemokine CCL2, Chemokine CCL3, Chemokine CCL4, Chemokine CCL5, Chemokine CXCL1, Chemokines, Chemokines, CXC, Chemotactic Factors, Female, Growth Substances, Humans, Immunoglobulins, Intravenous, Indium Radioisotopes, Intercellular Signaling Peptides and Proteins, Interleukin-8, Joints, Lectins, Leukocytes, Macrophage Inflammatory Proteins, Male, Middle Aged, Neutrophils, Radionuclide Imaging, Sialic Acid Binding Ig-like Lectin 2, Synovial Fluid, Synovial Membrane, T-Lymphocytes, Tumor Necrosis Factor-alpha