Commentary

Xenotransplantation: Risks, Clinical whether xenotransplantation as destination ther- apy can be successfully applied to humans. How- Potential, and Future Prospects ever, heart, kidney, and liver xenografts have been able to support human life for an extended period. The reemergence of xenotransplantation as a It is this fact that investigators wish to exploit in therapeutic option for the hundreds of thousands clinical bridging studies. By providing temporary of people dying each year of heart, kidney, lung, heart, kidney, or liver support as a bridge-to- and liver failure has raised ethical, social, and transplantation, these biological devices may al- scientific questions. End-stage organ failure is one low patients to recover end-organ function and of the most important public health problems fac- await allograft transplantation in a more stable ing Americans today. Heart failure, for example, clinical state, thus improving their chances of kills four times as many people as does HIV infec- survival. Bridging strategies cannot alleviate the tion and three times as many people as does breast human organ donor shortage. However, if one cancer; it is a disease with an increasing incidence, views bridging strategies as a first feasibility test, and the cost of taking care of affected patients is then cross-species transplantation does offer the 8 to 35 billion dollars each year. The single most effective therapy for it is transplantation. Preven- possibility of eventual long-term organ replace- tive therapies have had little impact on diseases ment. Success in this more ambitious goal would due to end-stage organ failure and are unlikely to help alleviate the human organ donor shortage. have an impact at least in the next decade. In the Nonhuman primate organ donors have been meantime, demand for organs, which far outstrips favored by those wishing to minimize the genetic the supply, continues to grow. It has been esti- disparity between donors and human recipients. mated that approximately 45,000 Americans un- Chimpanzees, although most compatible with der age 65 could benefit each year from heart standard selection criteria (e.g., compatibility of transplantation, yet only 2,000 human hearts are size and blood types), are unavailable as an ac- available annually. Patients are more likely to die ceptable source of clinical xenotransplantation. waiting for a human donor heart than in the first Another choice is the baboon, which is not endan- 2 years after transplantation. gered, has an anatomy and physiology similar to Although clearly an experimental procedure, those of humans, and grows to a weight of approxi- xenotransplantation between closely related spe- mately 70 pounds. Baboon size would limit the cies, such as baboons and humans, offers an alter- clinical application of xenotransplantation with native to allotransplantation as a source of human baboon organs to pediatric patients and small organ replacement. Alternatives to allograft do- adults. Small body size, the infrequency of blood nors, such as baboon or pig xenografts, require group O (universal donor) animals, and the lim- serious investigation if clinical transplantation is ited number of colony-bred animals are distinct ever to meet the current demand and continue the disadvantages to the baboon as a donor. explosive growth pattern it has established over Extended graft survival is possible, but ABO the past quarter century. blood group compatibility is mandatory before Biologic cardiac replacement poses the immu- xenotransplantation (2). The distribution of ABO nologic problems of rejection and infection associ- blood groups found in baboons indicates that ap- ated with transplantation. Increasing clinical proximately one third are group A, one-third experience worldwide has shown that rejection group B, and one-third group AB. Universal donor and infection can be managed successfully in most group O, however, is exceedingly rare. In Ameri- patients who receive human cardiac allografts. cans of Western European descent, the relative Further, the introduction of cyclosporine as the frequency of blood types is approximately 45% primary immunosuppressive agent for cardiac group A, 8% group B, 4% group AB, and 43% group transplant recipients has resulted in excellent O (2). survival rates (85% 1-year survival at most cen- Although available in large numbers, wild ba- ters) and has decreased illness associated with boons are not suitable from an infectious disease infection and rejection. Although considerable ad- perspective. Most experts have suggested that vances have been made in the field of cardiac colony-bred animals represent a more suitable xenotransplantation since its first clinical appli- donor pool. However, these animals number only cation by Hardy in 1964 (1), it remains uncertain in the hundreds and are, therefore, only likely to

Emerging Infectious Diseases 64 Vol. 2, No. 1 — January-March 1996 Commentary partially meet the epidemiologic demands of the Can one ever hope to determine if or when the pediatric population with end-stage organ failure. clinical application of xenotransplantation is jus- Xenotransplantation between baboons and hu- tified? The assessment of any experimental ther- mans raises the issue of xenozoonoses (3,4). The apy, as Fox and Swazey (6) have suggested, should organisms of greatest concern are the herpes- encourage the investigator to address three criti- viruses and retroviruses, which can be screened cal questions: 1) in the laboratory, what defines for and eliminated from the donor pool. Others “success” sufficient to warrant advancement to include Toxoplasma gondii, Mycobacterium tuber- the clinical arena? 2) under what clinical condi- culosis, and encephalomyocarditis virus. Less tions should this advancement proceed? and 3) in likely to be found in animals raised in captivity in the clinical arena, what defines “success” suffi- the United States are the filoviruses (Marburg cient to warrant further evaluation (6)? Providing and Ebola), monkeypox, and Simian hemorrhagic answers to this threefold inquiry requires a reli- fever virus. Organisms that are unlikely to be ance upon defined “success,” itself an appraisal of transmitted with an organ transplant (but should judgment that can only confidently be made in be screened for) include lymphocytic choriomen- retrospect. ingitis virus, gastrointestinal parasites, and GI Because human heart transplantation is now bacterial pathogens. considered by most justifiable for the treatment of The risk for xenozoonoses is likely to be re- end-stage heart disease, I would first like to re- stricted to the xenogeneic tissue recipient. Never- view the history of cardiac allotransplantation in theless, one must consider and anticipate the light of its ability to address the above threefold potential for xenozoonotic transmission through inquiry. I will also discuss the history of cardiac the human population, constituting a public xenotransplantation with reference to scientific health concern. The risk for recognized zoonotic advances made in the field throughout the past pathogens can be reduced, if not eliminated, by quarter century. Finally, in light of these analyses, controlling the donor animal vendor source and I hope to illustrate the role of baboon heart the individual donor animal by employing de- xenotransplantation as an alternative to allo- scribed screening tests and strict sterile proce- transplantation for permanent cardiac replace- dures during organ harvesting and donor autopsy ment in the treatment of end-stage heart disease. for tissue and blood. The risk for unrecognized After the first human cardiac allograft proce- pathogens is present but ill defined. dure performed by Barnard in 1967 (7) the field of Surveillance for the transmission of known or cardiac transplantation witnessed a surge in both unknown pathogens among health care workers enthusiasm and attempted trials, which was fol- must be conducted by monitoring for unexpected lowed by a marked drop in procedures throughout or unexplained adverse health events. It is diffi- the 1970s because of poor survival rates. During cult to monitor for the unknown; therefore, sur- the initial peak, 21 human heart allotransplants veillance should include notifying the principal were performed in the 6-month interval between investigator’s office of any unexplained illness in December 1967 and June 1968 (with a cumulative exposed health care workers, as well as telephone 1-year survival of 22%), and 105 cardiac allo- interviews of these personnel every 6 months by transplantations were performed in 1968 alone the principal investigator’s office. (8-10). However, these early clinical trials were marred by numerous failures, as 65% of persons Concurrent with scientific advances in undergoing the procedure before June 1970 died xenotransplantation have been the necessary within 3 months of transplantation (6). ethical debates concerning the appropriateness of this endeavor (5). Disputes regarding animal ex- Few centers continued animal research and perimentation notwithstanding, the ethical issues human procedures during the so-called black raised by many of these debates are strikingly years of cardiac transplantation. The initial explo- similar to those put forth 25 years ago in reference sion in clinical trials accordingly elicited numer- to the (then new) field of human heart transplan- ous responses suggesting that too much was being tation. Indeed, the timeless nature of these que- attempted too soon. ries itself attests to their essence, for such ethical Some would propose that this was the price of concerns are appropriate in the appraisal of any eventual “success,” and that further experimental new therapeutic procedure in medicine. studies at the time could not have avoided early

Vol. 2, No. 1 — January-March 1996 65 Emerging Infectious Diseases Commentary losses. And yet, there has been, and may always a cardiac transplant could be contemplated with be, a tacit recognition by medical innovators that hope of success” (7). Indeed, in their report of this the ultimate experiment must be performed in case, they further described the scientific basis of humans, for no animal model can truly reflect the their clinical advancement by explaining that human condition. Proponents of allotransplanta- “this achievement did not come as a surprise to tion at the time of the first heart transplantation the medical world. Steady progress toward this cited the more than 60-year history of experimen- goal had been made by immunologists, biochem- tal cardiac transplantation, beginning with Car- ists, surgeons, and specialists in other branches of rel’s original work in 1905. Although most of this medical science all over the world during the past work began in the 1930s, subsequent investiga- decades to ensure that this, the ultimate in car- tions regarding the experimental transplantation diac surgery, would be a success” (7). Although we of mammalian hearts showed that cardiac trans- may, in retrospect, consider them justified in their plantation was technically feasible and suggested declaration, in fact, at that time the endeavor was the possibility of clinically relevant survival rates. highly controversial and came as a surprise to During the decade before Barnard’s first clinical much of the medical world. application, cardiac allograft survival had been Second, under what conditions did they proceed shown to exceed 250 days (mean 103 days) in adult with this clinical trial? Given the “hope of suc- dogs treated with an immunosuppressive regimen cess,” Barnard and colleagues selected a patient that included azathioprine and methylprednisone “considered to have heart disease of such severity used intermittently. The mean survival in un- that no method of therapy short of cardiac trans- treated dogs used as controls was 7 days (11). plantation could succeed” (7). The patient, a 54- Since that time, with further expansion of year-old man, had remained in intractable knowledge in virtually all areas of clinical cardiac congestive heart failure (following multiple myo- transplantation, 1-year survival has increased cardial infarctions) despite all medical manage- from 67% in 1976, to approximately 85% reported ment (13). currently at most hospital centers (3). Human Finally, in this clinical arena, what defined for recipients have survived for as long as 20 years Barnard and colleagues “success” warranting fur- after transplantation, and the 10-year posttrans- ther investigation? A concurrent editorial in the plant survival rate is now approximately 45% (12). South African Medical Journal may provide some While these figures depict a clear improvement in insight into their thinking: “The claim ‘successful’ raw survival, cardiac transplantation is still not a can be used even at this early stage because to- cure for end-stage heart disease. Recipients must date it is a feat which makes medical history, no take immunosuppressive medication for life and matter how short the further survival of the pa- be monitored for infection, rejection, and graft tient might be (4). “Success,” by such an analysis, arteriopathy. However, these results are impres- was thus not targeted posttransplant survival sive considering that the recipient population to- time, but rather any posttransplant survival time day is considerably sicker than earlier allograft (given the ground-breaking nature of the en- candidates. In light of these findings, few would deavor). Further editorials regarding the ethics of deny cardiac allotransplantation its present claim cardiac transplantation viewed the procedure as to “success.” To further understand the evolution a legitimate experiment but not a treatment (15), of this achievement, however, we may now look while in 1968, the American College of Cardiology back upon the early years of cardiac allotransplan- suggested (with regard to the “success” of allo- tation and try to address the proposed threefold transplantation) that results varied: “. . . the spec- inquiry. trum of success ranges from short-term First, for Barnard and co-workers what can we restoration of circulation to complete physical re- presume as “success” warranting advancement to covery” (16). the clinical arena? They performed the first hu- Indeed, “success” did vary along a spectrum of man adult cardiac allotransplantation when the results. Barnard and colleagues’ first allotrans- maximum survival in immunosuppressed adult plant recipient lived for 18 days and ultimately dogs had been 250 days (average survival 103 died of pneumonia. However, their second recipi- days) (11) and suggested that “against the back- ent, 1 month later, survived more than 19 months ground of this research . . . the time arrived when before dying of chronic rejection (17). Their third

Emerging Infectious Diseases 66 Vol. 2, No. 1 — January-March 1996 Commentary patient also lived more than 20 months after allo- not been achieved experimentally. As Losman in transplantation and ultimately died of carcinoma an editorial regarding the Baby Fae experience of the stomach without signs of acute or chronic stated, “It appears that this baboon-to-infant rejection (18). One can only speculate how differ- transplantation did not rest on such a [scientific] ent the world reception to allotransplantation basis [as did Barnard’s earlier operation in 1967] would have been had the latter two patients rep- ”(28). resented the first and second recipients of cardiac During the past 3 years, investigators at the allotransplants. Would these survival data be con- University of Pittsburgh reported two cases in sidered “success,” or would they still pale in com- which they transplanted a baboon liver into a parison with the theoretical goal of obtaining a human recipient, obtaining a 70-day survival in graft that could function normally indefinitely? their first reported case, and a 26-day survival in Clinical cross-species transplantation dates to the second (29; J.J. Fung, pers. comm.) The inves- the early twentieth century, with kidney tigators’ overwhelming effort to prevent rejection xenografts from rabbit, pig, goat, non-human pri- led them to use a harsh immunosuppressive regi- mate and lamb donors (19). After these early fail- men that permitted multiple life-threatening ures, the scientific literature was largely devoid of infections. Rejection was not the major clinical reports of clinical xenotransplantation for nearly obstacle they encountered; therefore, they recom- 40 years. In 1963, Reemtsma and colleagues mended a more directed and less arduous immu- described six human recipients of chimpanzee kid- nosuppressive regimen for future patients. neys, the longest survivor of whom died of causes More alarming have been the attempts to apply unrelated to rejection 9 months after xenotrans- xenotransplantation of distantly related species plantation (20). to the clinical arena. In 1968, both Cooley and The first cardiac xenotransplantation, per- Ross transplanted sheep and pig hearts, respec- formed by Hardy in 1964, also represented the tively, into dying human recipients (30,31). Both first attempt at cardiac transplantation in hu- grafts failed upon reperfusion, presumably be- mans, predating Barnard’s report by nearly 4 cause of hyperacute rejection. years (1). Since 1964, when Hardy and colleagues More recently, Czaplicki and co-workers in at the University of Mississippi performed the 1992 described a case in which they attempted the world’s first heart xenotransplant using a chim- xenotransplantation of a pig heart into a human panzee as a donor, there have been eight docu- recipient with Marfan’s syndrome (32). By their mented attempts at clinical heart xeno- report, no evidence of hyperacute rejection was transplantation. Five of these donors were non- present at the time of death nearly 24 hours after human primates (2 baboons, 3 chimpanzees) and xenotransplantation. Their protocol used an un- three were domesticated farm animals (1 sheep, 2 usual immunosuppressive regimen in which both pigs) (21-25). The longest survivor was a newborn donor and recipient received, in addition to con- infant with hypoplastic left heart syndrome. ventional immunosuppression, both thymic tissue “Baby Fae” was the recipient of an ABO-blood extracts and fetal calf sera. This regimen also group mismatched baboon heart that functioned included the extracorporeal perfusion of two pig for 20 days (26). However, by the time the first hearts with the recipient’s blood in an attempt to human neonatal cardiac xenotransplantation was remove human anti-pig antibodies before the or- performed by Bailey in 1984 (the so-called “Baby thotopic transplantation of the functional pig Fae” case), there had been only limited experi- heart (33). As astonishing as this case may be in mental experience with prolonged graft survival its extension to the clinical arena of a technique in the newborn xenotransplant recipient. Studies not yet shown to be effective in the experimental presented by Bailey and co-workers shortly before laboratory, it is not unique. Also in 1992, Makowka the Baby Fae case described a mean survival time and colleagues transplanted a pig liver into a of 72 days in newborn lamb-to-goat xenotrans- 26-year-old woman dying of acute liver failure plants, with one survivor living to 165 days (27). from autoimmune hepatitis (pers. comm.). De- This advancement of xenotransplantation into spite the fact that, at present, it appears unlikely the clinical forum was met with resistance in the that sufficient “success” has been achieved in the medical community because of a perception that laboratory regarding xenotransplantation be- research with acceptable survival “success” had tween distantly related species to warrant

Vol. 2, No. 1 — January-March 1996 67 Emerging Infectious Diseases Commentary advancement to the clinical arena, these investi- must be more rigorous than our previous discus- gators were able to obtain approval from their sion. Indeed, the above comparison was put forth hospital’s ethics committee and institutional re- largely to underscore the more humble origins of view board to proceed with the clinical trial. Most the (now) successful therapy (allotransplantation) experts in the field of xenotransplantation share to which xenotransplantation is currently com- the opinion that pig-to-human organ transplanta- pared. tion remains at least 3 to 5 years from clinical What then defines “success” in the laboratory trials. warranting advancement from the laboratory to Considerable advances in the field of cardiac the operating room? Having demonstrated dra- xenotransplantation have subsequently emerged matic prolongation of cardiac xenograft survival worldwide since Hardy’s first clinical attempt in through experiments in rodent and non-human 1964, with a better understanding of the xenore- primate models (27,34-37), which model most jection process and a more sophisticated insight closely approximates the human condition (and into mechanisms for its control. Extended graft thus which therapy will be most successful in survival has been achieved in a number of differ- avoiding clinical rejection) remains to be estab- ent experimental models, including a greater than lished. Therefore, it is reasonable to suggest both tenfold graft survival in non-human primates that we have reached a formidable limitation for treated with conventional cyclosporine-based im- precisely predicting the applicability of experi- munosuppression (34,35) a more than thirtyfold mental laboratory evidence and that answers may increase in survival over controls described by only be sought from experiment in humans. This Celli and colleagues in a rodent model (36), and concept was realized by the American Medical survival beyond 1 year reported by Kawauchi and Association with regard to allotransplantation, in colleagues in a non-human primate model (37). reference to which it released an official statement These findings support the potential for achieving acknowledging this notion in 1969 (38). clinically relevant graft survival in humans. Concerns most commonly voiced with respect The question is whether we have reached a to the clinical application of xenotransplantation, stage in laboratory experimentation to justify fur- however, pertain to a larger ethical controversy ther attempts at advancing cardiac xenotrans- regarding human experimentation. Reemtsma, in plantation to the clinical arena. If we view the a related comment concerning the Baby Fae case, current status of experimental accomplishments suggested the following: “There is a widespread in xenotransplantation with the same scrutiny as misperception that medical treatments and surgi- that of allotransplantation at the time of Bar- cal procedures are easily classified as either ex- nard’s endeavor, we are left with similar conclu- perimental or accepted. In fact, all treatments sions; first, comparable graft survival time has have an element of experimentation, and new been achieved in animal models of xenotransplan- surgical procedures are based on extrapolations tation as was evident for allotransplantation be- from prior work. . . . When does a surgeon decide fore 1967. Second, with our current to apply a new operation to a patient? . . . the understanding of cardiac allotransplantation has decision is based on balancing, on the one hand, also come a greater awareness of its limitations. the experimental evidence suggesting that the Thus, the conditions for the advancement of procedure may succeed, and, on the other, the xenotransplantation arguably could be fulfilled by clinical urgency. . . (39). a patient with end-stage heart disease who is a Under what conditions will the clinical ad- candidate for allotransplantation, but for whom a vancement of xenotransplantation proceed? For donor cannot be identified in time. Finally, the those initial patients in whom clinical xenotrans- clinical “success” of xenotransplantation might plantation will first be applied, clinical urgency, in also be considered (as was the case for allotrans- the complete absence of other suitable alterna- plantation) any graft survival, and the goal of tives, undoubtedly will represent the motivating xenotransplantation to strive for extended graft factor to proceed. Who will comprise this initial survival. cohort? As Caplan has pointed out: “There would However, political and scientific sensibilities appear to exist a pool of terminally ill persons, today clearly differ from those of the 1960s, and so both children and adults for whom no therapeutic the critical assessment of xenotransplantation alternatives exist or are likely to exist in the near

Emerging Infectious Diseases 68 Vol. 2, No. 1 — January-March 1996 Commentary future. . . . It would [thus] appear ethically defen- mechanical circulatory support is limited both by sible to allow research involving xenografting in patient selection criteria and by the temporary human subjects to proceed in those areas where nature of the device. For excluded patients, as well no reasonable alternative to therapy exists (40). as many adult male candidates. For excluded pa- In this context, innumerable reservations have tients, cardiac xenotransplantation may be the been voiced regarding the ethics of proposing al- only reasonable alternative to cardiac allograft ternative experimental therapies to such patients replacement. for whom therapy has either failed or is non-exis- Investigations in clinical xenotransplantation tent. However, with regard to clinical experimen- have been accused of using “the guise of [being a] tation under these circumstances, one must also bridge-to-transplantation” to appear acceptable to recall (as Shimkin has suggested): “To do nothing, Institutional Research/Ethical Boards (5). How- or to prevent others from doing anything, is itself ever, the use of xenografts (or mechanical devices) a type of experiment, for the prevention of experi- solely as bridges to allotransplantation will not mentation is tantamount to the assumption of increase the donor pool, and, therefore, successful responsibility for an experiment different from permanent xenotransplantation must itself be the one proposed” (41). seen as the target for future clinical investiga- What is the goal of the clinical application of tions. The goal of these studies is thus not to xenotransplantation? The need for donor organs engage, as Hastillo and Hess (5) would suggest, in irrefutably outweighs the resources available, and the “premature use of unproven procedures in mechanical devices and xenotransplantation have fellow humans,” but rather to impact positively on emerged as the two most promising alternatives the current shortage of human donor organs (6). to allograft cardiac replacement. Mechanical left In 1996, the clinical picture is no less bleak and ventricular assist devices (LVADs) have witnessed the conclusions no less valid. The question that relative success as “bridges” in carefully selected remains is not how but rather when xenotrans- patients with heart failure. (A “bridge” is a tempo- plantation should advance to the clinical arena. rary method of life support designed to carry a Most of the uncertainties surrounding its ad- patient indefinitely until a human heart can be vancement will only be answered by its undertak- found and transplanted. It is not a “destination” ing. therapy.) In the foreseeable future, clinical xenotrans- Criteria for LVADs exclude patients with biven- plantation may achieve its targeted goal of ex- tricular failure, and (because of the relatively tended graft survival. As was the case during the large size of the device) patients with a total body early years of allotransplantation, clinical surface area less than 1.5 square meters (~120 lb). xenotransplantation must persevere under the Thus, many women and virtually all children are consideration of and often in spite of scrutiny by not candidates for mechanical left ventricular as- its most demanding critics, for while “success has sistance. As has been the case for Food and Drug a hundred fathers, failure is an orphan” (43). Administration protocols using LVADs, proposed Robert E. Michler Director of Heart Transplant Service investigations involving biologic assist devices Division of Cardiothoracic Surgery, (xenografts), have sought to evaluate a short-term Columbia-Presbyterian Medical Center, New York, NY, alternative to allotransplantation in patients for USA whom a donor heart is not immediately available, and death is imminent. Only candidates who meet criteria for heart transplantation, but do not meet References criteria for LVAD insertion, would be considered 1. Hardy JD, Chavez CM, Kurrus FE, et al. Heart trans- for a heart xenobridge. Similar clinical scenarios plantation in man: developmental studies and report have been proposed for other solid organ trans- of a case. JAMA 1964;188:114-22. plants. Since they were first introduced by Cooley 2. Wilson JD, et al., editors. Harrison’s Principles of in 1969, temporary mechanical circulatory sup- internal medicine, twelfth edition. New York: port devices have become critically useful tools in McGraw-Hill, Inc., 1991:1495. 3. Allan JS. Xenotransplantation at a crossroads: pre- the therapeutic armamentarium available to pa- vention vs. progress. Nature 1996;2:18-21. tients awaiting transplantation (42). Neverthe- 4. Michaels MG, Simmons RL. Xenotransplant-associ- less, at present, the widespread application of ated zoonoses. Transplantation 1994;57:1-7.

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