AN ANTAGONIST OF MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1) INHIBITS ARTHRITIS IN THE MRL-LPR MOUSE MODEL

An antagonist of human monocyte chemoattractant protein (MCP)-1, which consists of MCP-1(9-76), had previously been characterized and shown to inhibit MCP-1 activity in vitro. To test the hypothesis that, by in hibiting endogenous MCP-1, the antagonist has antiinflammatory activit y in vivo, we examined its effect in the MRL-lpr mouse model of arthri tis. This strain spontaneously develops a chronic inflammatory arthrit is that is similar to human rheumatoid arthritis. Daily injection of t he antagonist, MCP-1(9-76), prevented the onset of arthritis as monito red by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhan ced arthritis symptoms, indicating that the inhibitory effect is speci fic to the antagonist. In experiments where the antagonist was given o nly after the disease had already developed, there was a marked reduct ion in symptoms and histopathology, although individuals varied in the magnitude of the response. The mechanism of inhibition of disease is not known, although the results suggest that it could be more complex than the competitive inhibition of ligand binding that is observed in vitro. The demonstration of the beneficial effects of an MCP-1 antagon ist in arthritis suggests that chemokine receptor antagonists could ha ve therapeutic application in inflammatory diseases.