Madill-Thomsen Katelynn S, Gauthier Patrick T, Abouljoud Marwan, Bhati Chandra, Bruno David, Ciszek Michał, Durlik Magdalena, Feng Sandy, Foroncewicz Bartosz, Grąt Michał, Jurczyk Krzysztof, Levitsky Josh, McCaughan Geoff, Maluf Daniel, Montano-Loza Aldo, Moonka Dilip, Mucha Krzysztof, Myślak Marek, Perkowska-Ptasińska Agnieszka, Piecha Grzegorz, Reichman Trevor, Tronina Olga, Wawrzynowicz-Syczewska Marta, Zeair Samir, Halloran Philip F
Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
Henry Ford Hospital, Detroit, MI.
Transplantation. 2025 Aug 1;109(8):1367-1382. doi: 10.1097/TP.0000000000005269. Epub 2025 Jan 9.
Initial analysis of liver transplant biopsies in the INTERLIVER study ( ClinicalTrials.gov ; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population.
We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers.
The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities.
Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.
在国际肝脏移植研究（ClinicalTrials.gov；唯一标识符NCT03193151）中，对肝移植活检样本进行的初步分析使用与排斥反应相关的转录本，未能发现抗体介导的排斥反应状态（即富含自然杀伤细胞[NK]且有干扰素-γ效应）。我们最近在肺移植中开发了一种优化策略，分离出一种富含NK细胞的类似排斥反应（NKRL）状态，其在分子水平上与T细胞介导的排斥反应（TCMR）不同。在此，我们将相同策略应用于肝移植活检样本群体。
我们使用该策略在参与研究的国际中心收集的765份经同意的肝移植活检样本中寻找分子NKRL状态，这些样本进行了金标准组织学检查，并通过全基因组微阵列进行分子评估。通过训练集-测试集方法对优化选择的变量作为无监督排斥反应分类的输入进行验证，确定了肝脏中的NKRL状态。
完整模型将765份活检样本分为以下分子表型，以其基因表达为特征：无排斥反应占54%，TCMR占16%，NKRL占13%，损伤占16%。TCMR的顶级转录本在效应T细胞中表达；NKRL的顶级转录本几乎只在NK细胞中表达；两者的干扰素-γ诱导转录本均增加，在TCMR中更为明显。大多数TCMR活检样本有显著的实质损伤、分子纤维化和生化异常。NKRL活检样本没有过多的损伤、纤维化或生化异常。
优化的排斥反应算法表明，一些肝移植表现出NKRL状态，在活检后短期内耐受性良好，损伤最小且生化指标相对正常，同时也强调了TCMR导致广泛实质损伤的可能性。
