GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice

Objective: The pathogenic involvement of granulocyte- macrophage colony- stimulating factor ( GM- CSF) in arthritis has been put forward. We have investigated the therapeutic effect of GM- CSF neutralisation in the streptococcal cell wall ( SCW) arthritis model in mice. In this model, the pathogenic contribution of tumour necrosis factor ( TNF)alpha is minor and is expressed only on joint swelling, whereas cartilage proteoglycan depletion is independent of this cytokine. Methods: Acute monarthritis was induced by injection of SCW bacterial extracts to mouse knees. Treatments ( mAb 22E9 at 300, 100, 30 mu g; or Enbrel 300 mu g) were given twice intraperitoneally 2 h before and 3 days after disease induction. Swelling was assessed by Tc-99m uptake into knees on days 1 and 2. Local cytokine levels were determined in patellae washouts on day one. Proteoglycan loss from cartilage was scored on histological sections at termination on day four. Results: Treatment with anti- GM- CSF mAb 22E9 showed a dose- related efficacy by decreasing swelling that was significant at the 300 and 100 mg doses in comparison to isotype control, and comparable to dexamethasone ( 5 mg/ ml). Proteoglycan loss from cartilage was also significantly reduced by mAb 22E9 300 mg ( p = 0.001). This reduced proteoglycan loss observed after GM- CSF neutralisation was not seen after TNF alpha- blockade with Enbrel. Similarly, levels of interleukin 1 beta in joints were reduced after treatment with 22E9 mAb ( p = 0.003) but not in mice receiving Enbrel. Conclusions: Our findings show a pathogenic role for GM- CSF in this arthritis model, support the therapeutic potential of neutralising this cytokine, and may indicate therapeutic activity of an anti- GM- CSF mAb in TNF alpha-independent disease situations.