Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor α-independent mouse model

Objective: A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis ( RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy. Methods: A chronic relapsing arthritis was induced in C57BI/6 wild type (WT) and C57BI/6 genetically deficient for IL17 receptor (IL17R knockout ( KO)) mice by intraarticular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments ( intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators. Results: Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)alpha blockade had essentially no effect. Conclusion: Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNF alpha 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 TNF alpha inhibitors.