Objective: A pathogenic role for both GM-CSF and IL-17 in rheumatoid arthritis (RA) has been suggested. In previously published papers, we have described the therapeutic potentials of GM-CSF and IL-17 blockade in arthritis. In the present study, we have investigated the simultaneous blockade of both pathways in a mouse model for chronic arthritis to identify whether this double blockade provides a superior therapeutic efficacy.
Methods: A chronic relapsing arthritis was induced in C57Bl/6 wild-type (WT) and C57Bl/6 genetically deficient for IL-17 receptor (IL-17R KO) by intra-articular injection of SCW fragments into knees on days 0, 7, 14 and 21. Treatments (i.p.) were given weekly starting on day 14. Animals were analyzed for inflammation, joint damage and a range of inflammatory mediators.
Results: Joint swelling and cartilage damage were significantly reduced in the IL-17R KO mice and in WT mice receiving anti-GM-CSF neutralizing mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where both IL-17 and GM-CSF pathways were inhibited (e.g. IL-17R KO mice treated with 22E9 mAb). TNFα blockade had essentially no effect.
Conclusion: Our data further support the therapeutic potentials of GM-CSF and IL-17 blockade in a RA model that is no longer responsive to an established TNF£\ antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFα inhibitors.