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)α 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 μg; or Enbrel 300 μg) were given twice intraperitoneally 2 h before and 3 days after disease induction. Swelling was assessed by 99mTc 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 μg 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 μg (p = 0.001). This reduced proteoglycan loss observed after GM-CSF neutralisation was not seen after TNFα-blockade with Enbrel. Similarly, levels of interleukin 1β 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 TNFα-independent disease situations.
- CIA, collagen-induced arthritis
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- IL, interleukin
- PBS, phosphate-buffered-saline
- SCW, streptococcal cell wall
- TNF, tumour necrosis factor
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Published Online First 4 October 2006
Competing interests: CPZ, JH and PAB are full-time employees of Micromet AG.