Chemokine and chemokine receptor blockade in arthritis, a prototype of immune-mediated inflammatory diseases.

Chemokines and chemokine receptors have been implicated in inflammatory cell recruitment and angiogenesis underlying the pathogenesis of rheumatoid arthritis (RA) and other inflammatory rheumatic diseases. Numerous CXC, CC, C and CX3C chemokines and their receptors have been detected in the arthritic synovium and numerous strategies, including biologics, peptide and other small molecule inhibitors of chemokines and their receptors have given promising results in preclinical studies performed in animal models of arthritis. However, most recent human RA trials using antibodies and synthetic compounds have failed. Reasons for negative results of these RA trials include overlapping actions of multiple chemokines, dose-dependency, both antagonistic and agonistic effects of chemokines, chemokine degradation by proteases, as well as effects of anti-inflammatory, regulatory cells. Recent studies have suggested that CCR1 may still be a good target and previous trials may have failed because of the need of sustained CCR1 occupancy throughout the treatment. Therefore, modulation of receptor occupancy may be a feasible option to increase the efficacy of chemokine receptor targeting.