EFFECT OF A CC CHEMOKINE RECEPTOR ANTAGONIST ON COLLAGEN-INDUCED ARTHRITIS IN DBA 1 MICE/

Chemokines are small proteins that selectively activate and recruit le ukocytes to sites of inflammation. Several of them, including the CC c hemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC chemokin es IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium , implicating a potential role for these molecules in rheumatoid arthr itis. We have investigated the expression patterns of CC chemokine rec eptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration o f MetRANTES, a modified chemokine which is a nanomolar antagonist of c ertain CC chemokine receptors. The mRNA expression pattern of the chem okines and their receptors in the joints of arthritic mice was investi gated using reverse transcriptase-PCR and in situ hybridization. An up regulation of the CC chemokine receptors mCCR1, mCCR2, mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control anim als. In addition, injections of MetRANTES reduced the incidence of dis ease in a dose dependent manner. Furthermore, in MetRANTES-treated mic e that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstr ate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid ar thritis. (C) 1997 Elsevier Science B.V.