Postoperative Portal Hypertension Enhances Alloimmune Responses after Living-Donor Liver Transplantation in Patients and in a Mouse Model.

ABSTRACT

Controlling portal vein pressure in living-donor liver transplantation has received increased attention owing to its potential importance for graft survival. Portal hypertension may lead to the activation of liver-resident APCs, including liver sinusoidal endothelial cells (LSECs), which have immunological tolerogenic capacity. We investigated the effects of portal hypertension on graft survival and the antidonor immune response using clinical data and a mouse model. We categorized patients (n = 136) according to their portal vein pressure values at the end of surgery. Using propensity score-matching analyses, we found that portal hypertension was significantly associated with a higher antidonor immune response and incidence of acute rejection. To investigate the mechanism, we performed an allogeneic coculture assay using a 70% hepatectomized (HTx) mouse model with or without a portosystemic shunt. Liver cells from HTx mice without a shunt exhibited a significantly greater anti-BALB/c B6 T cell response than those from sham-operated mice or HTx mice with a shunt. LSECs from sham-operated mice, but not from HTx mice, suppressed the B6 T cell alloresponse in a dose-dependent manner. Furthermore, LSECs from HTx mice without a shunt showed significantly downregulated MHC class I/II and programmed death-ligand 1 expression, and those from mice with a shunt showed recovered expression of these molecules. Postoperative portal hypertension enhances alloimmune responses in recipients after living-donor liver transplantation, likely due, in part, to the impaired immune-suppression capacity of LSECs.