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.

中文翻译：

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肝移植活检排斥反应的分子诊断：INTERLIVER 研究的初步结果。

排斥反应的分子诊断正在肾脏、心脏和肺移植活检中出现，并可能为肝移植活检提供见解。我们通过微阵列测量了来自 10 个中心的 235 个肝移植活检组织中的基因表达。基于先前注释的排斥反应相关转录物表达的无监督原型分析确定了 4 组：正常“R1_正常”（N = 129），T 细胞介导的排斥反应（TCMR）“R2 _TCMR ”（N = 37），早期损伤“R3_损伤”（N = 61）和纤维化“R4_晚期”（N = 8）。移植后的中位时间各组不同，例如，R3_损伤99 天 vs R4_晚期3117 天。R2 _TCMR活检表达了典型的 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本（例如缺氧诱导因子 EGLN1）的表达增加。R4_晚期活检显示免疫球蛋白转录物和损伤相关转录物。R2 _TCMR与组织学排斥相关，尽管存在许多差异，而 R4与纤维化_{晚期相关。}R2 _TCMR、R3_损伤、R4_晚期与肝功能异常相关。受过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分数。人群中没有确诊的临床抗体介导排斥反应 (ABMR) 病例，之前在肾脏和心脏移植中揭示 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可检测排斥反应，有可能解决不明确的问题，并有助于免疫抑制管理。