The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study
The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study
复制标题
DOI：
10.1111/ajt.15828
复制
发表时间：
2020-08-01
影响因子：
8.8
通讯作者：
Halloran, Philip F.
中科院分区：
文献类型：
--
作者：
Madill-Thomsen, Katelynn;Abouljoud, Marwan;Halloran, Philip F.
排斥反应的分子诊断正在肾、心脏和肺移植活检中出现，并可能为肝移植活检提供见解。我们用微阵列技术检测了来自10个中心的235例肝移植活检标本的基因表达。基于先前注释的排斥相关转录物的表达的无监督原型分析鉴定了4组：正常“R1（正常）”（N = 129）、T细胞介导的排斥（TCMR）“R2（TCMR）”（N = 37）、早期损伤“R3（损伤）”（N = 61）和纤维化“R4（晚期）”（N = 8）。各组移植后中位时间不同，例如，R3（损伤）99天vs R4（晚期）3117天。R2（TCMR）活检表达典型的TCMR相关转录物，例如，强烈的IFNG诱导效应。R3（损伤）显示实质损伤转录物（例如，缺氧诱导因子EGLN 1）表达增加。R4（晚期）活检显示免疫球蛋白转录本和损伤相关转录本。R2（TCMR）与组织学排斥反应相关，尽管存在许多差异，R4（晚期）与纤维化相关。R2（TCMR）、R3（损伤）和R4（晚期）与肝功能异常相关。组织学排斥训练的监督分类器与组织学的一致性低于无监督R2（TCMR）评分。在人群中不存在临床抗体介导的排斥反应（ABMR）的确诊病例，并且先前在肾和心脏移植中揭示ABMR的策略未能揭示肝脏ABMR表型。总之，肝移植活检的分子分析检测排斥反应，有可能解决模棱两可的问题，并有助于免疫抑制治疗。
Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1(normal)" (N = 129), T cell-mediated rejection (TCMR) "R2(TCMR)" (N = 37), early injury "R3(injury)" (N = 61), and fibrosis "R4(late)" (N = 8). Groups differed in median time posttransplant, for example, R3(injury)99 days vs R4(late)3117 days. R2(TCMR)biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3(injury)displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4(late)biopsies showed immunoglobulin transcripts and injury-related transcripts. R2(TCMR)correlated with histologic rejection although with many discrepancies, and R4(late)with fibrosis. R2(TCMR), R3(injury), and R4(late)correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2(TCMR)scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.