Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders. Rheumatoid

arthritis (RA) is a common, chronic inflammatory disease, characterized by intense, destructive infiltration R788 of synovial tissue by a broad spectrum of inflammatory cells [1]. Multiple cytokines, derived from macrophages and fibroblasts, are responsible for induction of secretion of both cytokines and chemokines in RA [2]. The accumulation of leucocytes in the joint space leads to secretion of tissue degrading factors, including cytokines and matrix-degrading enzymes. Chemokines are small cytokines which act as chemoattractants for leucocytes, coordinating both homeostatic trafficking of these cells as well as recruiting GSK-3 inhibitor specific cell populations to sites of inflammation. Chemokine dysregulation is considered to play a part in a wide spectrum of human disease involving the immune system, including human

immunodeficiency virus (HIV) infection [3], malignancy [4] and autoimmunity [5]. The CC chemokine eotaxin-2/CCL11 binds to the eosinophil receptor CCR3, acting as a strong chemoattractant for eosinophils [6], basophils [7] and T helper type 2 (Th2) lymphocytes [8]. However, eotaxin-2 is not the sole ligand for CCR3, which can also be activated by regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) [9], monocyte

chemoattractant protein-3 (MCP-3) (CCL7) and MCP-4 (CCL13) [10]. CCR3, the eotaxin receptor, is a 7-transmembrane G protein-coupled receptor which is expressed by eosinophils, as well as by a wide array of cell types including macrophages and endothelial cells [11]. This chemokine is also expressed on human T helper cells [12]. CCR3 expression was originally studied extensively in the pathogenesis Ureohydrolase of asthma and allergy, where it continues to pose a therapeutic target [13]. More recently, however, a role for this pathway has emerged in the study of additional inflammatory and autoimmune disorders including inflammatory bowel disease [14], multiple sclerosis [15] and RA. Thus, CCR3 has been shown to play a role in recruitment of leucocytes to synovial tissue in adjuvant-induced arthritis (AIA), a commonly used animal model of RA [16]. In early AIA, CCR3 has been detected in synovial tissue macrophages and lining cells, with a subsequent trend towards declining expression [16]. This has been interpreted as reflecting a role for the eotaxin/CCR3 system in the initial trafficking of leucocytes into the synovial joint.