Ischemia-reperfusion Injury in Allogeneic Liver Transplantation: A Role of CD4 T Cells in Early Allograft Injury

Abstract

Background: A major discrepancy between clinical and most experimental settings of liver ischemia-reperfusion injury (IRI) is the allogenicity. Methods: 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. Results: 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. Conclusions: 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.