Leuven Lung Transplant Unit, Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, San Francisco, California, United States of America.
PLoS One. 2018 Oct 5;13(10):e0205107. doi: 10.1371/journal.pone.0205107. eCollection 2018.
Recent studies suggest that similar injury mechanisms are in place across different solid organ transplants, resulting in the identification of a common rejection module (CRM), consisting of 11 genes that are overexpressed during acute and, to a lesser extent, chronic allograft rejection.
We wanted to evaluate the usefulness of the CRM module in identifying acute rejection (AR) and different phenotypes of chronic lung transplant rejection (CLAD), i.e., bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), using transbronchial brushings, broncho-alveolar lavage (BAL) samples, and explant tissue.
Gene expression measurements for the 11 CRM genes (CD6, TAP1, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, and BASP1) were performed via qRT-PCR in 14 transbronchial brushings (AR, n = 4; no AR, n = 10), 32 BAL samples (stable, n = 13; AR, n = 8; BOS, n = 9; RAS, n = 10), and 44 tissue specimens (unused donor lungs, n = 15; BOS, n = 13; RAS, n = 16). A geometric mean score was calculated to quantitate overall burden of immune injury and a new computational model was built for the most significant genes in lung transplant injury.
Acute rejection showed a significant difference in almost every gene analysed, validating previous observations from microarray analysis. RAS tissue demonstrated a higher geometric mean score (6.35) compared to donor tissue (4.09, p = 0.018). Analysis of individual CRM genes showed an increased expression of ISG20, CXCL10 and CXCL9 in RAS. In BAL samples, no differences were detected in gene expression or geometric mean scores between the various groups (stable, 5.15; AR, 5.81; BOS, 5.62; RAS, 7.31). A newly modelled 2-gene tissue CRM score did not demonstrate any difference between BOS and RAS (p>0.05). However, the model was able to discriminate RAS from BOS tissue (AUC = 0.75, 95% CI = 0.55-0.94, p = 0.025).
Transcriptional tissue analysis for CRM genes in CLAD can identify acute rejection and distinguish RAS from BOS. The immune activation in RAS seems similar to acute rejection after kidney/liver/heart transplantation.
最近的研究表明，不同实体器官移植中存在类似的损伤机制，从而确定了一个共同的排斥模块（CRM），由 11 个基因组成，这些基因在急性排斥反应和在较小程度上在慢性移植物排斥反应中过度表达。
我们希望通过经支气管镜刷检、支气管肺泡灌洗（BAL）样本和移植组织评估 11 个 CRM 基因（CD6、TAP1、CXCL10、CXCL9、INPP5D、ISG20、LCK、NKG7、PSMB9、RUNX3 和 BASP1）的共同排斥模块（CRM）在识别急性排斥（AR）和慢性肺移植排斥（CLAD）的不同表型（即闭塞性细支气管炎综合征（BOS）和限制性移植物综合征（RAS））中的有用性。
通过 qRT-PCR 检测 14 例经支气管镜刷检（AR，n=4；无 AR，n=10）、32 例 BAL 样本（稳定，n=13；AR，n=8；BOS，n=9；RAS，n=10）和 44 例组织标本（未使用供体肺，n=15；BOS，n=13；RAS，n=16）中 11 个 CRM 基因的基因表达测量。计算几何平均评分以量化免疫损伤的总体负担，并为肺移植损伤中最重要的基因构建新的计算模型。
急性排斥反应在几乎每个分析的基因中均显示出显著差异，验证了先前微阵列分析的观察结果。RAS 组织的几何平均评分（6.35）明显高于供体组织（4.09，p=0.018）。对单个 CRM 基因的分析显示，RAS 中 ISG20、CXCL10 和 CXCL9 的表达增加。在 BAL 样本中，各组间基因表达或几何平均评分无差异（稳定，5.15；AR，5.81；BOS，5.62；RAS，7.31）。新建模的组织 CRM 2 基因评分不能区分 BOS 和 RAS（p>0.05）。然而，该模型能够区分 RAS 和 BOS 组织（AUC=0.75，95%CI=0.55-0.94，p=0.025）。
CLAD 中 CRM 基因的转录组织分析可识别急性排斥反应，并区分 RAS 和 BOS。RAS 中的免疫激活似乎与肾/肝/心脏移植后的急性排斥反应相似。
