Janssen Research & Development LLC, Spring House, Pa.
Institut Universitaire de Cardiologie et Pneumologie de Québec (IUCPQ), Quebec City, Quebec, Canada.
J Allergy Clin Immunol. 2017 Sep;140(3):710-719. doi: 10.1016/j.jaci.2016.11.038. Epub 2017 Jan 13.
The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects.
We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers.
IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression.
Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression.
A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.
气道疾病个体化治疗的表型研究（ADEPT）对轻度、中度和重度哮喘患者以及非变应性健康对照者进行了表型分析。
我们对该数据集进行了探索，根据气道黏膜 IL-13 驱动的基因表达来定义 2 型炎症，并研究其与临床可及的生物标志物的关系。
在几种人类细胞系中评估了 IL-13 驱动的基因表达。然后，根据气道黏膜（1）CCL26（差异表达最明显的基因）、（2）periostin 或（3）体外 IL-13 综合标志物（IVS）的表达，在 25 名健康受试者、28 名轻度哮喘患者、29 名中度哮喘患者和 26 名重度哮喘患者中定义 2 型状态。临床可及的生物标志物包括呼出气一氧化氮（Feno）值、血嗜酸性粒细胞（bEOS）计数、血清 CCL26 表达和血清 CCL17 表达。
气道黏膜 CCL26、periostin 和 IL-13-IVS 的表达均有助于将受试者分为 2 型高和 2 型低哮喘组，但在 ADEPT 研究人群中，CCL26 表达最佳。所有气道黏膜 CCL26 表达高且中重度哮喘患者的 Feno 值（≥35 ppb）和/或 bEOS 计数（≥300 个细胞/mm）均高于气道黏膜 CCL26 表达低的患者（36%）。Feno 值、bEOS 计数以及血清 CCL17 和 CCL26 表达的组合对气道黏膜 CCL26 高状态具有 100%的阳性预测值和 87%的阴性预测值。2 型高和 2 型低状态受试者的临床变量无差异。嗜酸性粒细胞炎症与气道黏膜 2 型基因表达相关，但不仅限于此。
一组临床生物标志物可根据气道黏膜 CCL26、periostin 或 IL-13-IVS 基因表达准确分类 2 型状态。联合使用 Feno 值、bEOS 计数和血清标志物水平（如 CCL26 和 CCL17）可能有助于为新型 2 型治疗方法选择患者。
