Clinical Trials and the Projected Future of Liver Xenotransplantation

The trial and error of the pioneering xenotransplant trials over the past three decades has defined the limitation of the species used. Success was tantalizingly close with the chimpanzee, baboon, and other primates. The use of more disparate species has been frustrated by the xenoantibody barrier. Future attempts at clinical xenotransplantation will be hampered by the consideration of the species of animals and the nature of the organs to be transplanted. On one hand, primate donors have the advantage of genetic similarity (and therefore potential compatibility) and less risk of Immunologic loss. On the other hand, pig donors are more easily raised, are not sentient animals, and may be lli:ss likely to harbor transmissible disease. It is recognized that the success of xenotransplantation may very with dlft'erent organs. Because it is relatively resistant to antibody-mediated rejection, the liver is the organ for which there is the greatest chance of long-term success. Consideration of using xenotransplants on a temporary basis, or as a "bridge" to permanent human transplantation. may allow clinical trials utilizing hearts or kidney xenografts. Issues on metabolic compatibility and infection risks cannot be accurately determined until routine success in clinical xeno· transplantation occurs. Based on a limited experience, the conventional approaches to allotransplantation are unlikely to be successful in xenotransplantation. The avoidance of immediate xenograft destruction by hyperacute rejection, achieved using transgenic animals bearing human complement regulatory proteins or modulating the antigenic target on the donor organ, is the first step to successful xenotransplantation. The ability to achieve tolerance by establishing a state of bone marrow chimerism is the key to overcoming the long-term immunologic insults and avoiding the necessarily high doses of nonspecific immunosuppression that would otherwise be required and associated with a high risk of infectious complications. Xenotransplantation faces criticish"1 that is strongly reminiscent of that leveled against human-to-human transplantation during the late 19605 and early 19705. Yet with persistence, the field of human·to·human transplantation has proved highly successful. This success was the result of a stepwise increase in our understanding of the biology of rejection, Improvements in drug management, and experience. It is possible that xenotransplantation may not be universally successful until further technologic advances occur; yet cautious exploration of xenotransplantation appears warranted to identify those areas that !"eq!.~!~ !!!~!!e!" :~!!!,fS Organ transplantation has become an effective means for treating patients with end-stage organ failure. This achievement can be largely attributed to the development of advanced technical skills and the availability of new immunosuppressive agents. such as cyclosporine and tacrolimus. Patients undergoing organ transplantation experience excellent likelihood of survival with good Correspondence to: J. Fung. M.D .. Ph.D. quality of life. This success has increased the demand for organ transplantation, and thus an estimated 75,000 Americans suffering from end-stage organ failure currently await or receive a lifesaving organ transplantation each year. However, almost 10% of patients awaiting transplantation die because of the lack of availability of human organs each year [1]. Despite heightened public awareness to address the need for organ donation, there appears to be little prospect of increasing donation to meet the current needs. It is widely anticipated that the only means of addressing this shortage is by the development of artificial organs or utilizing organs from species other than humans (or both) and has inspired concerted research efforts in the field of xenotransplantation. Although artificial organs may become reality with future developments, their ability to replace complex organs, such as the liver, is probably years away. Without the benefit of artificial support of patients with liver, heart, or lung failure, transplantation of functioning organs is the only alternative to death. Thus xenotransplantation represents the most promising alternative to the current organ shortage, especially with an increased understanding of rejection mechanisms of both allografts (organs transplanted across the same species) and xenografts (organs transplanted across different species). Recent developments in understanding the barriers to successful xenotransplantation have led to the application of novel drugs to manipulate the immune system. Along with the concept of microchimerism applied to xenotransplantation and bolstered by the utilization of genetically modified donor animals, application of new bioreagents to enhance microchimerism holds promise for future attempts at clinical xenotransplantation.