GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice
GM-CSF neutralisation suppresses inflammation and protects cartilage in acute streptococcal cell wall arthritis of mice
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DOI：
10.1136/ard.2006.057182
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发表时间：
2007-04-01
影响因子：
27.4
通讯作者：
van den Berg, W. B.
中科院分区：
文献类型：
--
作者：
Plater-Zyberk, C.;Joosten, L. A. B.;van den Berg, W. B.
目的：探讨粒细胞-巨噬细胞集落刺激因子（GM-CSF）在关节炎发病中的作用.我们研究了GM-CSF中和在小鼠链球菌细胞壁（SCW）关节炎模型中的治疗效果。在这个模型中，肿瘤坏死因子（TNF）α的致病贡献是轻微的，只在关节肿胀，而软骨蛋白多糖耗竭是独立的，这种cytokine.Methods：急性monarthritis引起的SCW细菌提取物注射到小鼠膝关节。在疾病诱导之前2小时和之后3天腹膜内给予两次治疗（300、100、30 μ g的mAb 22 E9;或Enbrel 300 μ g）。在第1天和第2天通过膝关节的Tc-99 m摄取来评估肿胀。在第一天测定髌骨冲洗中的局部细胞因子水平。结果：用抗GM-CSF单克隆抗体22 E9治疗显示了剂量相关的疗效，通过减少肿胀，与同种型对照相比，在300和100 mg剂量下显著，与地塞米松（5 mg/ ml）相当. mAb 22 E9 300 mg也显著降低了软骨的蛋白聚糖损失（p = 0.001）。在GM-CSF中和后观察到的这种减少的蛋白聚糖损失在用Enbrel阻断TNF α后没有观察到。类似地，关节中的白细胞介素1 β水平在用22 E9 mAb治疗后降低（p = 0.003），但在接受Enbrel.Conclusions的小鼠中没有降低：我们的发现显示了GM-CSF在该关节炎模型中的致病作用，支持中和该细胞因子的治疗潜力，并且可能表明抗GM-CSF mAb在TNF α非依赖性疾病情况中的治疗活性。
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.