Dissertation

Discordant liver xenotransplantation in recipients with liver failure

Tector, A Joseph

2003

Overview

Liver xenotransplantation could eliminate the liver donor shortage, but currently it is not possible because of a lack of understanding of liver xenograft rejection. Hyperacute xenograft rejection is initiated by the binding of preformed naturally occurring xenoreactive antibodies (XNA) to the xenograft endothelium. The XNA bind to the xenograft endothelium, leading to complement-mediated endothelial injury. Liver xenotransplantation will be initially offered to patients with severe liver failure as a bridge to a human liver transplantation. The hypothesis tested in this thesis is that hyperacute rejection of liver xenografts placed into recipients with liver failure will be diminished because of the complement deficiency that accompanies liver failure. The experiments described in this thesis detail the development of an in vitro pig-to-human liver xenotransplant model incubating cultured pig hepatic endothelial cells (PHEC) and human serum in culture. We showed that either classical or alternative complement pathways could initiate endothelial injury. Next we developed the dog-to-pig liver xenograft model and characterized the lethal coagulopathy that results from hyperacute rejection. The coagulopathy results from the lack of function of platelets as well as their disappearance from the circulation. We then used the galactosamine induced liver injury model in porcine recipients of canine liver xenografts to demonstrate that hyperacute rejection in the setting of liver failure is diminished. We showed that; tissue injury, coagulopathy and platelet defect, and endothelial injury were diminished. Our experiments suggested that the cause of the decreased injury was the lack of complement in the pigs with galactosamine induced liver injury since the XNA levels were no different than in control animals. Our final experiments evaluated serum from patients with liver failure and compared the injury caused by incubation with PHEC. Serum from the liver failure patients had similar levels of XNA when compared with normal subjects, but had less complement activity, and less C3 and C4. Incubation of liver failure serum with PHEC caused much less injury and complement activation than serum from control subjects. The results in this thesis suggest that liver failure will have a significant impact on liver xenograft rejection, helping to diminish hyperacute rejection.

• Publisher: ProQuest Dissertations & Theses
• Subject: Anatomy & physiology / Animals / Cellular biology / Medicine / Physiology / Surgery
• ISBN: 9780612885868, 0612885860