EVIDENCE THAT PORTAL TRACT MICROVASCULAR DESTRUCTION PRECEDES BILE-DUCT LOSS IN HUMAN LIVER ALLOGRAFT-REJECTION

In liver allograft rejection, interlobular bile ducts are thought to be the main target of rejection. In contrast, in other organ allografts the capillary bed of the graft appears to be the primary target. To determine whether portal tract microvasculature is destroyed in liver allografts during rejection, we have identified portal tract microvasculature in 11 normal livers and 38 liver allograft biopsy specimens using monoclonal antibodies to capillary endothelium in immunohistochemical staining. E1.5, CD31 and EL-4 antibodies identified portal microvascular endothelium in normal liver that had the morphology of capillaries. In allograft biopsies the number of microvascular structures per portal tract was reduced markedly in acute cellular rejection to 1.1+/-0.6 (n=25) and to 0.65+/-0.9 (n=15) in chronic ductopenic rejection compared with nonrejecting allografts (2.8+/-0.6) (n=4) or normal liver (3.8+/-0.7) (n=11). To determine whether loss of microvascular structures preceded bile duct destruction in rejection, sections were double-stained to identify both microvasculature and bile ducts. The number of microvascular structures per bile duct was significantly lower in acute cellular rejection (0.5+/-0.4) (n=18) or chronic rejection (0.3+/-0.4)(n=8) compared with normal liver (2.3+/-0.6) (n=7) (P<0.0001), demonstrating that components of the portal vasculature are destroyed prior to bile ducts. There was a correlation between the severity of rejection and the loss of microvascular structures per bile duct (P<0.001). In conclusion, in common with other allografted organs, the microvasculature of liver allografts appears to be an early target of rejection.