气道上皮细胞 IL-17A 反应特征可识别出一类对类固醇治疗无应答的 COPD 患者亚群。
An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.
机构信息
Department of Medicine, UCSF, San Francisco, California, USA.
University Medical Center Groningen, Department of Pulmonary Diseases and Research Institute for Asthma and COPD (GRIAC), Groningen, Netherlands.
出版信息
J Clin Invest. 2019 Jan 2;129(1):169-181. doi: 10.1172/JCI121087. Epub 2018 Nov 26.
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype.
METHODS
We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids.
RESULTS
The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation.
CONCLUSION
These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01969344.
FUNDING
Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.
背景
慢性阻塞性肺疾病（COPD）是一种异质性的与吸烟相关的疾病，其特征为气道阻塞和炎症。这种炎症甚至可能在戒烟后持续存在，并对皮质类固醇的反应存在差异。针对生物学上相似的“分子表型”进行个体化治疗可能会提高 COPD 的治疗效果。IL-17A 参与中性粒细胞炎症和皮质类固醇耐药性，因此在 COPD 的分子表型中可能尤为重要。
方法
我们从有和无 COPD 的吸烟者（n=238）的支气管气道上皮刷片中生成了 IL-17A 反应的基因表达特征，并使用银屑病中 IL-17 阻断的 2 项随机试验的数据进行了验证。在 COPD 的另外 2 项人类研究中，该 IL-17 特征与临床和病理特征有关：（a）SPIROMICS（n=47），其中包括患有和未患有 COPD 的前吸烟者和现吸烟者，以及（b）GLUCOLD（n=79），其中 COPD 参与者被随机分配至安慰剂或皮质类固醇。
结果
IL-17 特征与以 IL-17 反应为特征的炎症特征相关，包括气道中性粒细胞和巨噬细胞增加。在 SPIROMICS 中，该特征与定量胸部 CT 上气道阻塞和小气道功能障碍的增加有关。在 GLUCOLD 中，该特征与皮质类固醇反应降低有关，而与气道嗜酸性粒细胞或 2 型炎症无关。
结论
这些数据表明，IL-17 气道上皮反应的基因特征可区分生物学、影像学和临床上不同的 COPD 亚组，这些亚组可能受益于个体化治疗。
试验注册
ClinicalTrials.gov NCT01969344。
资金
主要由 NIH 提供支持，资助项目包括 K23HL123778、K12HL11999、U19AI077439、DK072517、U01HL137880、K24HL137013 和 R01HL121774，以及合同 HHSN268200900013C、HHSN268200900014C、HHSN268200900015C、HHSN268200900016C、HHSN268200900017C、HHSN268200900018C、HHSN268200900019C 和 HHSN268200900020C。
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