Danger Richard, Royer Pierre-Joseph, Reboulleau Damien, Durand Eugénie, Loy Jennifer, Tissot Adrien, Lacoste Philippe, Roux Antoine, Reynaud-Gaubert Martine, Gomez Carine, Kessler Romain, Mussot Sacha, Dromer Claire, Brugière Olivier, Mornex Jean-François, Guillemain Romain, Dahan Marcel, Knoop Christiane, Botturi Karine, Foureau Aurore, Pison Christophe, Koutsokera Angela, Nicod Laurent P, Brouard Sophie, Magnan Antoine
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.
Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
Front Immunol. 2018 Jan 11;8:1841. doi: 10.3389/fimmu.2017.01841. eCollection 2017.
Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (), T-cell leukemia/lymphoma protein 1A (), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.
闭塞性细支气管炎综合征（BOS）是慢性肺移植功能障碍的主要表现，会导致肺移植后长期生存率低下。识别BOS的预测指标对于在不可逆转的损害发生之前预防功能障碍的进展至关重要。通过使用来自肺移植受者的107个样本的大型数据集，我们对全血进行了微阵列基因表达谱分析，以识别BOS的早期生物标志物，包括来自49名功能稳定至少3年的患者的样本、在BOS诊断前至少6个月收集的32个样本（预测组）以及在BOS诊断时或之后的26个样本（诊断组）。来自25名肺移植受者的独立数据集用于通过定量PCR进行验证（13名功能稳定者、11名在预测组以及8名在诊断组）。我们鉴定出在功能稳定者和BOS受者之间差异表达的50个转录本。三个基因，即POU2关联因子1（）、T细胞白血病/淋巴瘤蛋白1A（）和B细胞淋巴细胞激酶，被验证为在诊断前6个月以上的BOS预测生物标志物，曲线下面积分别为0.83、0.77和0.78。这些基因允许基于BOS风险进行分层（对数秩检验＜0.01），并且与移植后时间无关。这是首次发表的肺移植后血液的大规模基因表达分析。这三种基因的血液特征可为临床医生提供新工具，以改善对可能发生BOS的患者的随访并调整治疗方案。
