ILAR Journal Online, Volume 37(1) 1995: Perspective on Xenotransplantation

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ILAR Journal V37(1) 1995
Perspectives on Xenotransplantation

Introduction
Ralph B. Dell

Ralph B. Dell, M.D., is an IACUC chairman, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York.

Many physicians, patients, and their families hope that animal to human transplantation could become an option for individuals with critical organ failure for whom no human organs are available. Xenotransplantation has been tried several times in the past 10 years without long term success. For example, baby Fae and, more recently, baboon-to-human liver transplants at the University of Pittsburgh have attracted considerable attention. These experiments and the shortage of human organs have combined to spur research on xenotransplantation. At the same time, the prospect of using animal organs in people has stimulated much interest in the public and among thoughtful observers, raising a number of ethical, legal, social, and scientific issues. There is considerable hope that with further research and experimentation the technique can become a viable option for desperately ill people.

Nonetheless, confusion, doubt, controversy and opposition have led to fear that xenotransplantation will result in chimeric monsters. There is some theological and philosophical opposition. Some of these fears are groundless and should be calmed with better public education while other concerns should be and are being discussed and debated in many different forums. Ethicists and philosophers have debated the proper conduct of human experimentation and the use of animals in research which has lead to careful review procedures for both humans and animals.

There is concern that xenotransplantation hasn't worked and won't work and that it is too expensive or is a misallocation of scarce resources. Economic arguments for and against xenotransplantation involve questions of proper resource allocation and the cost of human life, questions which are not easily answered. Another aspect of the cost issue is quality of life, an important consideration for all considering receiving grafts.

Interest in xenotransplantation has sparked considerable immunological research which has significantly improved the probability of success. Rejection of transplanted organs is now recognized to occur in several stages with each stage representing numerous and complex biochemical reactions. While there are many similarities among the immune systems of mammals, the details of the human immune system will require study of humans. Many of the proteins involved in immune reactions are species-specific. Therefore, detection and quantification of these proteins requires species-specific reagents. There is also hope that transgenic animals will express human proteins and modify the response to the transplanted organ by the human immune system.

The possibility that organ transplantation from animals can transmit infectious disease to humans is of concern. This possibility warrants careful consideration and merits taking precautions to protect the public health. The precise nature of these precautions will have to be decided by experts in infectious and emerging diseases. It should also be recognized that no monitoring scheme will be able to guard against the unknown.

The use of animal organs in the treatment of human disease has raised significant issues in a number of spheres. Thoughtful discussion and communication with the public and its representatives are needed with all of these concerns.

In this first issue of ILAR Journal, seven authors, chosen to represent a diversity of views, consider many of the concerns raised by the prospect of xenotransplantation research in humans. These concerns include ethical, legal, and social issues; the current status of immunological research; and the possible infectious disease consequences of using either nonhuman primates or other species as donor animals.

All of these issues are of interest and concern to both the institutional animal care and use committee (IACUC), which reviews the use of animals, and the institutional review board (IRB), which reviews the use of human subjects in research, at institutions that are contemplating research on xenotransplantation, either direct organ transplant, tissue implantation, or various extracorporeal devices containing animal tissue. Consideration must be given to the issues discussed in this report in order to adequately review the proposed experiment. Furthermore, these experiments have facility and husbandry implications, raise regulatory issues, and cause the concerned people to grapple with understanding the ethical, legal, social, and scientific issues of xenotransplantation. This issue of ILAR Journal provides an overview that is a beginning to understanding this complex and developing area of research.

In the opening article, Charles McCarthy reviews the ethical, legal, and social issues surrounding the use of xenografts in humans. While he supports the use of animals in research, he points out that the complexities go far beyond the use of animals. He outlines conditions that should be met for approval from the IACUCs and IRBs, and from the institution itself. All of these conditions require careful thought and discussion by all concerned: committee members, investigative staff, and institutional officials.

Keith Reemtsma reviews the history of xenotransplantation from ancient Greece to the present, including his own considerable contributions to the field through studies in both humans and nonhuman primates. He concludes that the most difficult question is when to transfer work from the laboratory to the clinical setting. The decision to proceed must be made on an individual basis (including, it might be added, discussion with local committees and accounting for public concerns), but, as Reemtsma goes on to state, "clinical success is probable, although not assured, in the near future." In contrast, David Steele and Hugh Auchincloss Jr. believe that animals used in laboratory trials of xenotransplantation have not yet reached the length of survival that justifies moving to human experimentation. The authors assert that more work is needed to understand rejection of xenogeneic tissue and, at a minimum, they want to see long-term survival in animal studies before proceeding to human cases. Thus, the current state of knowledge concerning the immunologic response to xenografts is raised as a potential barrier to proceeding with human studies.

The immunology of transplantation is reviewed in two complementary articles by David Sachs and Jeffrey Platt. Sachs focuses on cellular and serologic mechanisms in both concordant (between similar species) and discordant (between species phylogenetically disparate) xenotransplants. The author notes that because there are many immunosuppressive drugs available, long-term results may depend on increasing the recipient's tolerance to the graft. Platt provides the reader with a thorough review of antibody- and complement-mediated xenograft rejection. Because there are immunological responses to organs transplanted from nonhuman primates, there is a hyper-acute response to organs from animals such as swine, which are phylogenetically far from human. This hyper-acute rejection of swine organs involves complement reaction to certain cell surface proteins. Using transgenic techniques, these proteins can be made to be more like human proteins. Swine have a number of desirable features as organ donors if hyperacute rejection can be overcome.

The final section explores the likelihood that a virulent organism may be transferred from the animal to the xenograft recipient. For some, this is a theoretical issue that can be safely ignored. For others, the potential consequences are so great that xenotransplantation should not be performed unless there are compelling reasons for doing so. Many agree that cautiously proceeding with xenotransplantation research in humans is appropriate given the shortage of human donors and the need to do immunologic research in human xenotransplantation. Seymour Kalter and R.L. Heberling provide an overview that explains why there is a concern but state that thus far infectious disease has been a minor factor in transplantation. Jonathan Allan takes a more cautious view of transmission of organisms and the likelihood of the occurrence of disease. In his view, transfer of organisms is bound to occur, but the question really is--will it be harmful? He ends with a call for the formation of a panel of experts to address these issues.

Just such a workshop is being planned by the Institute of Medicine (IOM) of the National Academy of Sciences. Currently in the planning stages (see summary p. 50 by Dr. Constance Pechura, associate director the Division of Behavioral Sciences and Mental Disorders of the IOM), the 3-day workshop will cover many of the issues considered in this edition of ILAR Journal, including a full day devoted to the infectious disease problem and ways of minimizing the potential threat to the public health. In addition, a number of federal agencies, including the Food and Drug Administration, the Centers for Disease Control and Prevention, National Institutes of Health, and Health Resources Services Administration, and a number of professional societies are interested in a study of the issues raised by xenotransplantation. The IOM workshop will be held on June 25 to 27, 1995.

The success of transplantation in treating life-threatening organ failure has exceeded the supply of human organs, despite concerted efforts by many organizations to recruit donors. The need to turn to nonhuman animals for organs raises a host of complex ethical, social, and scientific issues that must be considered by all those contemplating working in this difficult area. Many of these issues are dealt with in this first edition of ILAR Journal and will be further addressed by the IOM workshop. Clearly, with issues as complicated as these, there will be ongoing discussion for a number of years.