The Research Of TIM-1Signaling Attenuates Liver Ischemia-reperfusion Injury In Mouse Orthotopic Liver Transplantation

Background:Hepatic injury due to prolonged ex-vivo cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4T cell TIM-1signaling co-sTIMulates a variety of immune responses in allograft recipients.Aims:This study analyzes mechanisms by which TIM-1affects liver ischemia-reperfusion injury (IRI) in a clinically relevant murine model of prolonged cold storage followed by OLT.Methods:Livers from C57BL/6mice, preserved at4℃in UW solution for20h, were transplanted to syngeneic recipients. There was an early (lh) increased accumulation of TIM-1+activated CD4T cells in the ischemic OLTs.Results:Disruption of TIM-1signaling with a blocking mAb (RMT1-10) ameliorated liver damage at6h, evidenced by reduced sALT levels and well-preserved OLT architecture. Unlike in control group, TIM-1blockade diminished OLT expression of Tbet/IFN-y, but amplified IL-4/IL-10/IL-22levels; abolished intrahepatic neutrophil and macrophage infiltration/activation; and inhibited NF-kB while enhancing anti-apoptotic Bcl-2/Bcl-xl. Although adoptive transfer of CD4T cells triggered fulminant liver damage in otherwise IR-resistant RAG-/-mice, adjunctive TIM-1blockade reduced Tbet transcription, and abolished macrophage activation, ulTIMately restoring homeostasis in IR-stressed livers.Conclusions:TIM-1expressing CD4T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLT recipients.