The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/7/131/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 1, July 7, 1997 131-137

Articles

An Antagonist of Monocyte Chemoattractant Protein 1 (MCP-1) Inhibits Arthritis in the MRL-lpr Mouse Model

Jiang-Hong Gong*, Leslie G. Ratkay{ddagger}, J. Douglas Waterfield{ddagger}, and Ian Clark-Lewis*

From the * Biomedical Research Centre and Department of Biochemistry and Molecular Biology, and {ddagger} Department of Oral Biology and Department of Microbiology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

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 inhibiting endogenous MCP-1, the antagonist has antiinflammatory activity in vivo, we examined its effect in the MRL-lpr mouse model of arthritis. This strain spontaneously develops a chronic inflammatory arthritis that is similar to human rheumatoid arthritis. Daily injection of the antagonist, MCP-1(9-76), prevented the onset of arthritis as monitored by measuring joint swelling and by histopathological evaluation of the joints. In contrast, controls treated with native MCP-1 had enhanced arthritis symptoms, indicating that the inhibitory effect is specific to the antagonist. In experiments where the antagonist was given only after the disease had already developed, there was a marked reduction 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 antagonist in arthritis suggests that chemokine receptor antagonists could have therapeutic application in inflammatory diseases.

Address correspondence to Dr. Ian Clark-Lewis, Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Phone: 604-822-7805; FAX: 604-822-7815; E-mail: ian{at}brc.ubc.ca

1Abbreviations used in this paper: CCR, human CC chemokine receptor; MCP, monocyte chemoattractant protein; RA, rheumatoid arthritis.


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