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肿瘤坏死因子α阻断剂在抗中性粒细胞胞浆抗体相关性血管炎和肾小球肾炎中是否起作用?

Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis?

作者信息

McAdoo Stephen P, Pusey Charles D

机构信息

Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.

出版信息

Nephrol Dial Transplant. 2017 Jan 1;32(suppl_1):i80-i88. doi: 10.1093/ndt/gfw361.

Abstract

Tumour necrosis factor alpha (TNFα) is a cytokine that is pivotal in the inflammatory response. Blockade of TNFα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFα in the pathophysiology of disease, including increased expression of TNFα mRNA in leucocytes and in renal tissue. Importantly, TNFα can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNFα enhances glomerular injury and TNFα blockade using soluble TNFα receptor or anti-TNFα antibody ameliorates disease. Mice deficient in TNFα are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNFα antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNFα antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNFα antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNFα antibody. There are several clinical studies demonstrating a response to anti-TNFα antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNFα antibody was the only change in treatment. We suggest that further investigation of TNFα blockade in AAV is warranted.

摘要

肿瘤坏死因子α(TNFα)是一种在炎症反应中起关键作用的细胞因子。已证明阻断TNFα在包括类风湿性关节炎在内的多种人类自身免疫性疾病中有效,这就提出了该方法在炎症性肾脏疾病(如抗中性粒细胞胞浆抗体相关性血管炎(AAV))中是否有效的问题。在AAV中,有大量证据表明TNFα在疾病病理生理学中起作用,包括白细胞和肾组织中TNFα mRNA表达增加。重要的是,TNFα可诱导血管炎相关自身抗原(蛋白酶3和髓过氧化物酶(MPO))在白细胞细胞膜上表达,从而使细胞对抗中性粒细胞胞浆抗体的作用产生致敏。在抗肾小球基底膜疾病(肾毒性肾炎)的啮齿动物模型中,TNFα会加重肾小球损伤,使用可溶性TNFα受体或抗TNFα抗体阻断TNFα可改善疾病。缺乏TNFα的小鼠对肾毒性肾炎具有抵抗力,且这种作用主要取决于肾脏固有细胞。脂多糖可增强抗MPO抗体诱导的肾小球肾炎小鼠模型的病变,而抗TNFα抗体可阻断这种作用。在由MPO诱导的AAV大鼠模型(实验性自身免疫性血管炎)中,抗TNFα抗体可改善肾脏病理状况,并减少白细胞迁移,活体显微镜检查已证实这一点。在临床研究中,韦格纳肉芽肿病依那西普试验(WGET)表明,与标准治疗相比,额外使用依那西普并无益处。然而,WGET研究结果不排除在急性肾AAV中使用抗TNFα抗体,原因有几个,包括研究设计以及依那西普和抗TNFα抗体作用之间存在的显著生物学差异。有多项临床研究表明,抗TNFα抗体对常规治疗无效的AAV患者有疗效,在其中一些研究中,添加抗TNFα抗体是治疗中唯一的改变。我们认为有必要对AAV中TNFα阻断进行进一步研究。

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