Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
Tumour necrosis factor (TNFα) as a novel therapeutic target in symptomatic corticosteroid dependent asthma
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DOI：
10.1136/thx.2005.045260
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发表时间：
2005-12-01
期刊：
影响因子：
10
通讯作者：
Holgate, ST
中科院分区：
文献类型：
--
作者：
Howarth, PH;Babu, KS;Holgate, ST
背景：肿瘤坏死因子α (TNF α)是一系列慢性炎性疾病的主要治疗靶点，其特征是Th1型免疫反应，其中TNF α过量产生。相比之下，哮喘被认为是一种Th2型疾病，特别是当与特应性反应有关时。然而，随着哮喘变得更加严重和慢性，它采用了额外的特征，包括皮质类固醇难愈性和中性粒细胞的参与，这表明炎症谱发生了改变，导致Th1型反应，包括TNF α等细胞因子。方法：采用免疫分析法测定26例健康对照、42例轻度哮喘和20例重度哮喘患者支气管肺泡灌洗液中TNF α的水平，并测定14例轻度哮喘和14例重度哮喘患者支气管活检标本中TNF α基因的表达。免疫组化法检测肿瘤坏死因子α的细胞定位。然后对17名严重哮喘患者进行了一项开放标签非对照临床研究，以评估可溶性TNF α受体- IgG(1)Fc融合蛋白依那西普治疗12周的效果。结果：严重皮质类固醇依赖性哮喘患者BAL液中TNF - α水平、TNF - α基因表达和TNF - α免疫反应细胞升高。依那西普治疗与哮喘症状、肺功能和支气管高反应性改善相关。结论：这些发现可能对确定TNF α作为治疗重症哮喘的新靶点具有临床意义。抗肿瘤坏死因子治疗的效果现在需要在安慰剂对照研究中得到证实。
Background: Tumour necrosis factor alpha (TNF alpha) is a major therapeutic target in a range of chronic inflammatory disorders characterised by a Th1 type immune response in which TNF alpha is generated in excess. By contrast, asthma is regarded as a Th2 type disorder, especially when associated with atopy. However, as asthma becomes more severe and chronic, it adopts additional characteristics including corticosteroid refractoriness and involvement of neutrophils suggestive of an altered inflammatory profile towards a Th1 type response, incriminating cytokines such as TNF alpha.Methods: TNF alpha levels in bronchoalveolar lavage (BAL) fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma were measured by immunoassay, and TNF alpha gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma. The cellular localisation of TNF alpha was assessed by immunohistochemistry. An open label uncontrolled clinical study was then undertaken in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNF alpha receptor- IgG(1)Fc fusion protein, etanercept.Results: TNF alpha levels in BAL fluid, TNF alpha gene expression and TNF alpha immunoreative cells were increased in subjects with severe corticosteroid dependent asthma. Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness.Conclusions: These findings may be of clinical significance in identifying TNF alpha as a new therapeutic target in subjects with severe asthma. The effects of anti- TNF treatment now require confirmation in placebo controlled studies.