Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury.
Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury.
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同种异体肝移植缺血再灌注损伤：CD4T细胞在移植肝早期损伤中的作用
DOI：
10.1097/tp.0000000000003488
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发表时间：
2021-09-01
期刊：
影响因子：
6.2
通讯作者：
Zhai Y
中科院分区：
文献类型：
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作者：
Kageyama S;Kadono K;Hirao H;Nakamura K;Ito T;Gjertson DW;Sosa RA;Reed EF;Kaldas FM;Busuttil RW;Kupiec-Weglinski JW;Zhai Y
肝脏缺血再灌注损伤（IRI）的临床和大多数实验设置之间的主要差异是同种异体性。在本研究中，我们首先建立了延长冷缺血时间（18h）的同种异体原位肝移植（alloc - olt）小鼠模型。采用消耗性抗CD4抗体测定CD4 T细胞在同种异体肝移植缺血再灌注损伤（IRI）发病机制中的作用。回顾性分析55例肝移植患者CD4作为肝脏IRI标志物的临床相关性。通过血清转氨酶水平和肝脏组织学测量，供体和受体的CD4耗损都能最有效地保护同种异体肝移植物免受IRI的侵害。CD4耗竭抑制ir诱导的移植物内中性粒细胞/巨噬细胞浸润和促炎基因表达。人肝活检（灌注后2h）的定量RT-PCR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。当我们根据移植体内CD4水平将患者分为亚组时，高CD4组比低CD4组出现更严重的肝细胞损伤。CD4 T细胞在异基因肝移植IRI中起着关键的致病作用，灌注后早期移植内CD4水平可作为改善肝脏IRI和改善OLT结果的潜在生物标志物和治疗靶点。
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 (allo-OLT) with extended cold ischemia time (18h). Roles of CD4 T cells in the pathogenesis of ischemia reperfusion injury (IRI) in liver allografts was determined using a depleting anti-CD4 Ab. 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 intra-graft neutrophil/macrophage infiltration and pro-inflammatory gene expressions. Quantitative RT-PCR analysis of human liver biopsies (2h postreperfusion) revealed that post-, rather than pre-, transplant CD4 transcript levels correlated positively with pro-inflammatory gene expression profile. When we divided patients into sub-groups according to intra-graft 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 intra-graft CD4 levels in the early postreperfusion phase may serve as a potential biomarker and therapeutic target to ameliorate liver IRI and improve OLT outcomes.