Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, University of California, Los Angeles, CA.
Department of Biostatistics, UCLA School of Public Health, University of California, Los Angeles, CA.
Transplantation. 2021 Sep 1;105(9):1989-1997. doi: 10.1097/TP.0000000000003488.
A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity.
In the current study, we first established a murine model of allogeneic orthotopic liver transplantation with extended cold ischemia time (18 h). Roles of CD4 T cells in the pathogenesis of IRI in liver allografts were determined using a depleting anti-CD4 antibody. The clinical relevance of CD4 as a marker of liver IRI was analyzed retrospectively in 55 liver transplant patients.
CD4 depletion in both donors and recipients resulted in the most effective protection of liver allografts from IRI, as measured by serum transaminase levels and liver histology. CD4 depletion inhibited IR-induced intragraft neutrophil/macrophage infiltration and proinflammatory gene expressions. Quantitative reverse-transcriptase polymerase chain reaction analysis of human liver biopsies (2 h postreperfusion) revealed that posttransplant, rather than pretransplant, CD4 transcript levels correlated positively with proinflammatory gene expression profile. When we divided patients into subgroups according to intragraft CD4 levels, the high CD4 cohort developed a more severe hepatocellular damage than that with low CD4 levels.
CD4 T cells play a key pathogenic role in IRI of allogeneic liver transplants, and intragraft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve orthotopic liver transplantation outcomes.
临床和大多数肝缺血再灌注损伤 (IRI) 的实验环境之间存在一个主要差异，即异源性。
在本研究中，我们首先建立了一个具有延长冷缺血时间（18 小时）的同种异体原位肝移植的小鼠模型。使用耗竭性抗 CD4 抗体来确定 CD4 T 细胞在肝移植物 IRI 发病机制中的作用。回顾性分析了 55 例肝移植患者中 CD4 作为肝 IRI 标志物的临床相关性。
供体和受者的 CD4 耗竭导致肝移植物对 IRI 的保护最有效，这可以通过血清转氨酶水平和肝组织学来衡量。CD4 耗竭抑制了 IR 诱导的肝内中性粒细胞/巨噬细胞浸润和促炎基因表达。对人肝活检（再灌注后 2 小时）的定量逆转录聚合酶链反应分析显示，移植后而不是移植前，CD4 转录水平与促炎基因表达谱呈正相关。当我们根据肝内 CD4 水平将患者分为亚组时，高 CD4 组比低 CD4 组发生更严重的肝细胞损伤。
CD4 T 细胞在同种异体肝移植的 IRI 中发挥关键的致病作用，再灌注后早期肝内 CD4 水平可能作为一种潜在的生物标志物和治疗靶点，以改善肝 IRI 并改善原位肝移植的结果。
