GM-CSF neutralization suppresses inflammation and protects cartilage in acute Streptococcal Cell Wall arthritis of mice

C Plater-Zyberk ^1*, L AB Joosten ², M MA Helsen ², J Hepp ¹, P Baeuerle ¹ and W B van den Berg ³

¹ Micromet AG, Germany
² Rheumatology Research Laboratory and Advanced Therapeutics, Netherlands
³ University Hospital Nijmegen, Netherlands

^* To whom correspondence should be addressed. E-mail: christine.plater-zyberk{at}micromet.de.

Accepted 26 September 2006

Abstract

Objective: A pathogenic involvement for GM-CSF in arthritis has been put forward. We have investigated the therapeutic effect of GM-CSF neutralization in the Streptococcal Cell Wall arthritis (SCW) model in mice. In this model, the pathogenic contribution of TNF& [alpha] is minor and only on joint swelling, whereas cartilage proteoglycan depletion is independent of this cytokine.

Methods: Acute mono-arthritis was induced by injection of SCW bacterial extracts to mouse knees. Treatments (mAb 22E9 at 300, 100, 30 µg; or Enbrel& [reg] 300 µg) were administered twice i.p. 2 hours prior and 3 days after disease induction. Swelling was assessed by 99mTc uptake into knees on days 1 & 2. Local cytokine levels were determined in patellae washouts on day 1. Proteoglycan loss from cartilage was scored on histological sections at termination on day 4.

Results: Treatment with anti-GM-CSF mAb 22E9 showed a dose-related efficacy at 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 neutralization was not seen after TNF-blockade with Enbrel®. Similarly, levels of IL-1 in joints were reduced after treatment with 22E9 mAb (p=0.003) but not in mice receiving Enbrel®.

Conclusions: Our findings demonstrate a pathogenic role for GM-CSF in this arthritis model, support the therapeutic potential of neutralizing this cytokine, and may indicate therapeutic activity of an anti-GM-CSF mAb in TNF-independent disease situations.

Keywords: GM-CSF, SCW arthritis, cytokine, disease model, treatment

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