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

Abstract

The pathophysiological state of rejection in liver xenotransplantation is poorly understood. Data from clinical pig liver perfusion suggest that pig livers might be rejected less vigorously than pig hearts or kidneys. Pig livers used in clinical xenoperfusions were exposed to blood from patients with liver failure. We have shown in an animal model that transplant recipients 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 diminished capacity of the patient with liver failure to respond to xenogeneic tissue. Pathological analysis of the perfused pig livers showed immunoglobulin M deposition in the sinusoids with little evidence of complement activation. Our in vitro studies showed that serum from patients with liver failure caused less injury to pig liver endothelium than serum from healthy subjects. Serum from patients with liver failure had similar levels of xenoreactive antibodies as serum from healthy humans. Incubation of serum from patients 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. (Liver Transpl 2001;7:82-89.)

Aberrations in hemostasis and coagulation in untreated discordant hepatic xenotransplantation: Studies in the dog-to-pig model

“…The decreased levels of complement that accompany liver failure might explain these changes in coagulation system function. 9,24,25 Platelets can be activated by exposure to the subendothelium.…”

Pig Liver Xenotransplantation as a Bridge to Allotransplantation: Which Patients Might Benefit?

“…Importantly, in both in vitro experiments and in animal models, it has been demonstrated that a potential recipient with severe liver failure would be less capable of initiating hyperacute rejection of a xenograft than a healthier recipient (73,74). Furthermore, there is currently no evidence that a prior pig xenograft will sensitize a patient to a subsequent allograft (reviewed in Cooper et al, 2004) (75).…”

Immunobiology of liver xenotransplantation

“…Recipient survival was limited to 7 days due to the rapid development of severe thrombocytopenia, resulting in spontaneous hemorrhages in various native organs and tissues, and in the liver xenograft [13,29]. Thrombocytopenia developed within 1 h post-transplantation (in previous experiments reported by Tector et al in a model of dog-to-pig liver xenotransplantation, thrombocytopenia occurred within 15 min post-transplantation) [38,39]. Despite immediate thrombocytopenia, liver function was documented near-normal to normal (as assessed by liver enzymes, coagulation factors, coagulation assays and production of porcine-specific proteins) [37].…”