Rejection of pig liver xenografts in patients with liver failure: Implications for xenotransplantation

The pathophysiological state of rejection in liver xenotransplantation is p oorly understood. Data from clinical pig liver perfusion suggest that pig l ivers might be rejected less vigorously than pig hearts or kidneys. Pig liv ers used in clinical xenoperfusions were exposed to blood from patients wit h liver failure. We have shown in an animal model that transplant recipient s with liver failure are less capable of initiating hyperacute rejection of a xenografted liver than a healthy transplant recipient. The goal of this report is to examine the pathological characteristics of pig livers used in 2 clinical pig liver perfusions and combine this information with in vitro studies of pig-to-human liver xenotransplantation to determine whether the findings in the perfused pig livers could be explained in part by the dimi nished capacity of the patient with liver failure to respond to xenogeneic tissue. Pathological analysis of the perfused pig livers showed immunoglobu lin M deposition in the sinusoids with little evidence of complement activa tion. Our in vitro studies showed that serum from patients with liver failu re caused less injury to pig liver endothelium than serum from healthy subj ects. Serum from patients with liver failure had similar levels of xeno-rea ctive antibodies as serum from healthy humans. Incubation of serum from pat ients with liver failure with pig hepatic endothelial cells generated less iC3b, Bb fragment, and C5b-9 than serum from healthy subjects. We conclude that the altered injury in the perfused pig livers can be attributed to the relative complement deficiency that accompanies liver failure.