Weigt S Samuel, Wang Xiaoyan, Palchevskiy Vyacheslav, Gregson Aric L, Patel Naman, DerHovanessian Ariss, Shino Michael Y, Sayah David M, Birjandi Shirin, Lynch Joseph P, Saggar Rajan, Ardehali Abbas, Ross David J, Palmer Scott M, Elashoff David, Belperio John A
Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California, United States of America.
PLoS One. 2017 Jan 19;12(1):e0169894. doi: 10.1371/journal.pone.0169894. eCollection 2017.
Chronic Lung Allograft Dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Although CLAD is usually not responsive to treatment, earlier identification may improve treatment prospects.
In a nested case control study, 1-year post transplant surveillance bronchoalveolar lavage (BAL) fluid samples were obtained from incipient CLAD (n = 9) and CLAD free (n = 8) lung transplant recipients. Incipient CLAD cases were diagnosed with CLAD within 2 years, while controls were free from CLAD for at least 4 years following bronchoscopy. Transcription profiles in the BAL cell pellets were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression analysis, based on an absolute fold change (incipient CLAD vs no CLAD) >2.0 and an unadjusted p-value ≤0.05, generated a candidate list containing 55 differentially expressed probe sets (51 up-regulated, 4 down-regulated).
The cell pellets in incipient CLAD cases were skewed toward immune response pathways, dominated by genes related to recruitment, retention, activation and proliferation of cytotoxic lymphocytes (CD8+ T-cells and natural killer cells). Both hierarchical clustering and a supervised machine learning tool were able to correctly categorize most samples (82.3% and 94.1% respectively) into incipient CLAD and CLAD-free categories.
These findings suggest that a pathobiology, similar to AR, precedes a clinical diagnosis of CLAD. A larger prospective investigation of the BAL cell pellet transcriptome as a biomarker for CLAD risk stratification is warranted.
慢性肺移植功能障碍（CLAD）是肺移植后长期生存的主要限制因素。尽管CLAD通常对治疗无反应，但早期识别可能会改善治疗前景。
在一项巢式病例对照研究中，从早期CLAD患者（n = 9）和无CLAD患者（n = 8）的肺移植受者中获取移植后1年的监测支气管肺泡灌洗（BAL）液样本。早期CLAD病例在2年内被诊断为CLAD，而对照组在支气管镜检查后至少4年无CLAD。使用HG-U133 Plus 2.0微阵列（Affymetrix）检测BAL细胞沉淀中的转录谱。基于绝对倍数变化（早期CLAD与无CLAD）>2.0和未调整的p值≤0.05进行差异基因表达分析，生成了一个包含55个差异表达探针集的候选列表（51个上调，4个下调）。
早期CLAD病例的细胞沉淀倾向于免疫反应途径，主要由与细胞毒性淋巴细胞（CD8 + T细胞和自然杀伤细胞）的募集、滞留、激活和增殖相关的基因主导。层次聚类和监督机器学习工具都能够将大多数样本（分别为82.3%和94.1%）正确分类为早期CLAD和无CLAD类别。
这些发现表明，在CLAD临床诊断之前存在一种类似于急性排斥反应的病理生物学过程。有必要对BAL细胞沉淀转录组作为CLAD风险分层生物标志物进行更大规模的前瞻性研究。
