Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice
Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice
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DOI：
10.1038/sj.ki.5002103
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发表时间：
2007-04-01
影响因子：
19.6
通讯作者：
Heeringa, P.
中科院分区：
文献类型：
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作者：
Huugen, D.;van Esch, A.;Heeringa, P.
在小鼠中，小鼠抗髓过氧化物酶（MPO）IgG的管理诱导缺乏免疫坏死性新月体肾小球肾炎。最近对该模型的研究表明，补体激活在疾病诱导中发挥着至关重要的作用。在此，我们研究了在抗MPO IgG诱导的肾小球肾炎小鼠模型中，用C5抑制性单克隆抗体（BB5.1）进行预处理或干预的效果。小鼠在用抗MPO IgG和脂多糖诱导疾病之前8小时或之后1天接受BB 5.1。1天或7天后处死小鼠。对照抗体预处理的小鼠出现血尿、白细胞尿和白蛋白尿，以及肾小球肾炎，平均21.0 +/- 8.8%肾小球新月体和12.8 +/- 5.5%肾小球毛细血管坏死。BB5.1预处理防止了疾病发展，如通过不存在尿异常、第1天肾小球中性粒细胞流入的显著减少和第7天的正常肾形态所证明的。重要的是，疾病诱导后1天给予BB5.1也导致尿异常的显著减弱和肾小球新月体形成的超过80%的减少。总之，在抗MPO IgG诱导的肾小球肾炎小鼠模型中，抑制C5活化可减弱疾病的发展。这些结果有利于进一步研究补体激活在人MPO-抗中性粒细胞胞质自身抗体介导的肾小球肾炎中的作用，并表明抑制C5激活是这种疾病的潜在治疗方法。
In mice, administration of murine anti-myeloperoxidase (MPO) IgG induces pauci-immune necrotizing crescentic glomerulonephritis. Recent studies in this model indicate a crucial role for complement activation in disease induction. Here, we investigated the effect of pretreatment or intervention with a C5- inhibiting monoclonal antibody (BB5.1) in the mouse model of anti-MPO IgG-induced glomerulonephritis. Mice received BB5.1 8 h before or 1 day after disease induction with anti-MPO IgG and lipopolysaccharide. Mice were killed after 1 or 7 days. Control antibody-pretreated mice developed hematuria, leukocyturia and albuminuria, and glomerulonephritis with a mean of 21.0 +/- 8.8% glomerular crescents and 12.8 +/- 5.5% glomerular capillary necrosis. BB5.1 pretreatment prevented disease development, as evidenced by the absence of urinary abnormalities, a marked reduction in glomerular neutrophil influx at day 1 and normal renal morphology at day 7. Importantly, BB5.1 administration 1 day after disease induction also resulted in a marked attenuation of urinary abnormalities and a more than 80% reduction in glomerular crescent formation. In conclusion, inhibition of C5 activation attenuates disease development in a mouse model of anti MPO IgG-induced glomerulonephritis. These results favor further investigations into the role of complement activation in human MPO-anti-neutrophil cytoplasmic autoantibody-mediated glomerulonephritis, and indicate that inhibition of C5 activation is a potential therapeutic approach in this disease.