Xenotransplantation: still a bridge too far?

The spread of hepatitis viruses, increasing levels of obesity, and increasing levels of alcohol consumption worldwide have led to an increase in the incidence of cirrhosis, hepatocellular carcinoma, and liver failure (1). Orthotopic liver transplant is often the only possibility for cure, but the number of cadaveric donor organs available remains insufficient to meet the demand. Attempts at bridging orthotopic liver transplant with hepatocyte transplantation, bioartificial liver devices or extracorporeal pig liver perfusion have been met with limited success. Xenotransplantation may offer a solution for a potentially limitless pool of organs. Non-human primates would provide an optimal source of organs, but there are a number of disadvantages: breeding such animals would be slow, difficult, and costly; there has been little research into their genetic modification; and the risk of transmission of infectious agents is higher in the more closely related donor and recipient species (2). Perhaps more importantly, the use of such intelligent sentient animals, many of which are endangered, would pose ethical issues. Thus, the ability to transplant a genetically modified pig liver could overcome many of these problems. Pigs are already used as a source for insulin and heart valves, and as such, their use as a source of organs is unlikely to raise objections. There are two major issues to be overcome if pig to human liver xenotransplantation is to be successful: rejection and function. Rejection after xenotransplantation has several phases. Hyperacute rejection, occurring within minutes, is brought about by the presence of preformed antibodies principally against the polysaccharide antigen galactosyl -(1,3)-galactosyl -1,4-N-acetyl glucosaminyl or gal epitope. Humans do not express this epitope but are exposed to the antigen through the gut, and therefore, they produce antigal antibodies. The production of -1,3-galactosyltransferase knockout pigs (3), which do not express the gal epitope, has been a significant step toward the use of pig livers for xenotransplantation. Acute humoral xenograft rejection, within 24 hr, is mediated by IgM and later IgG antibodies to the gal epitope and other antigens (4). Finally, although the adaptive immune response is similar to that after allotransplantation, there are greater peptide differences between different species than between members of the same species, and so, the potential for indirect xenogeneic responses is much higher. Therefore, higher levels of immunosuppression may be required (2). The second hurdle to overcome is to ensure that the xenotransplant provides sufficient function to replace the failing liver. The transplanted liver must not only produce sufficient levels of key proteins but these also need to function in the human recipient. For example, porcine renin and erythropoietin do not function in humans. The liver produces numerous proteins, many of which may not be compatible across species (2). Ekser et al. (5) have previously transplanted 1,3galactosyltransferase knockout pig livers into baboons using immunosuppressive agents, demonstrating minimal evidence of rejection posttransplant. In their current study (6), they addressed the issue of graft function. They have mostly concentrated on porcine clotting factors and shown evidence of their production in the baboon. Although the level of many of these was below normal pig levels, suggesting the liver was not functioning normally, they were near normal for baboons. This, combined with the fact that clinical measures of coagulation such as international normalized ratio remained normal, suggests that the porcine coagulation factors were functional in the baboon. The authors also looked at complement levels that remained high, suggesting production by the transplanted liver. Conversely, total protein and albumin levels decreased to normal pig levels, significantly lower than those for baboons and humans, soon after transplant. This raises the issue that to what extent is the function of a xenotransplanted liver predetermined by the species of origin or by the species into which it is transplanted. Clinical observation of baboons posttransplant revealed that they remained well with no signs of encephalopathy. Encouragingly all baboons were successfully extubated and appeared well with normal feeding and behavior posttransplant. Liver function did become deranged with increased aspartate aminotransferase, -glutamyl transferase (GT), and alkaline phosphatase (ALP) in several baboons, and total or direct bilirubin also increased, possibly due to abnormally viscous bile leading to cholestatic injury. As stated by the authors, this has been described previously but may not pose a problem in pig to human transplant, as pig and human bile are of similar viscosity (7). More worryingly, Centre for Liver Research, University of Birmingham/Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, West Midlands, United Kingdom. Address correspondence to: David C. Bartlett, M.B.Ch.B., M.R.C.S., Centre for Liver Research, University of Birmingham/Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, United Kingdom. E-mail: d.c.bartlett@bham.ac.uk Received 6 May 2010. Accepted 24 May 2010. Copyright © 2010 by Lippincott Williams & Wilkins ISSN 0041-1337/10/9005-481 DOI: 10.1097/TP.0b013e3181e98d6a