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Copy to clipboard. Although the potential benefits are considerable, the use of xenotransplantation raises concerns regarding the potential infection of recipients with both recognized and unrecognized infectious agents and the possible subsequent transmission to their close contacts and into the general human population. Of public health concern is the potential for cross-species infection by retroviruses, which may be latent and lead to disease years after infection.
Moreover, new infectious agents may not be readily identifiable with current techniques. Xenotransplantation between baboons and humans raises the issue of xenozoonoses 3 , 4. The organisms of greatest concern are the herpesviruses and retroviruses, which can be screened for and eliminated from the donor pool. Others include Toxoplasma gondii , Mycobacterium tuberculosis , and encephalomyocarditis virus. Less likely to be found in animals raised in captivity in the United States are the filoviruses Marburg and Ebola , monkeypox, and Simian hemorrhagic fever virus.
Organisms that are unlikely to be transmitted with an organ transplant but should be screened for include lymphocytic choriomeningitis virus, gastrointestinal parasites, and GI bacterial pathogens. The risk for xenozoonoses is likely to be restricted to the xenogeneic tissue recipient. Nevertheless, one must consider and anticipate the potential for xenozoonotic transmission through the human population, constituting a public health concern.
The risk for recognized zoonotic pathogens can be reduced, if not eliminated, by controlling the donor animal vendor source and the individual donor animal by employing described screening tests and strict sterile procedures during organ harvesting and donor autopsy for tissue and blood.
The risk for unrecognized pathogens is present but ill defined. Surveillance for the transmission of known or unknown pathogens among health care workers must be conducted by monitoring for unexpected or unexplained adverse health events.
It is difficult to monitor for the unknown; therefore, surveillance should include notifying the principal investigator's office of any unexplained illness in exposed health care workers, as well as telephone interviews of these personnel every 6 months by the principal investigator's office. Concurrent with scientific advances in xenotransplantation have been the necessary ethical debates concerning the appropriateness of this endeavor 5.
Disputes regarding animal experimentation notwithstanding, the ethical issues raised by many of these debates are strikingly similar to those put forth 25 years ago in reference to the then new field of human heart transplantation. Indeed, the timeless nature of these queries itself attests to their essence, for such ethical concerns are appropriate in the appraisal of any new therapeutic procedure in medicine.
Can one ever hope to determine if or when the clinical application of xenotransplantation is justified? The assessment of any experimental therapy, as Fox and Swazey 6 have suggested, should encourage the investigator to address three critical questions: 1 in the laboratory, what defines "success" sufficient to warrant advancement to the clinical arena?
Providing answers to this threefold inquiry requires a reliance upon defined "success," itself an appraisal of judgment that can only confidently be made in retrospect. Because human heart transplantation is now considered by most justifiable for the treatment of end-stage heart disease, I would first like to review the history of cardiac allotransplantation in light of its ability to address the above threefold inquiry.
I will also discuss the history of cardiac xenotransplantation with reference to scientific advances made in the field throughout the past quarter century. Finally, in light of these analyses, I hope to illustrate the role of baboon heart xenotransplantation as an alternative to allotransplantation for permanent cardiac replacement in the treatment of end-stage heart disease. After the first human cardiac allograft procedure performed by Barnard in 7 the field of cardiac transplantation witnessed a surge in both enthusiasm and attempted trials, which was followed by a marked drop in procedures throughout the s because of poor survival rates.
Few centers continued animal research and human procedures during the so-called black years of cardiac transplantation.
The initial explosion in clinical trials accordingly elicited numerous responses suggesting that too much was being attempted too soon. Some would propose that this was the price of eventual "success," and that further experimental studies at the time could not have avoided early losses. And yet, there has been, and may always be, a tacit recognition by medical innovators that the ultimate experiment must be performed in humans, for no animal model can truly reflect the human condition.
Proponents of allotransplantation at the time of the first heart transplantation cited the more than year history of experimental cardiac transplantation, beginning with Carrel's original work in Although most of this work began in the s, subsequent investigations regarding the experimental transplantation of mammalian hearts showed that cardiac transplantation was technically feasible and suggested the possibility of clinically relevant survival rates.
During the decade before Barnard's first clinical application, cardiac allograft survival had been shown to exceed days mean days in adult dogs treated with an immunosuppressive regimen that included azathioprine and methylprednisone used intermittently. The mean survival in untreated dogs used as controls was 7 days While these figures depict a clear improvement in raw survival, cardiac transplantation is still not a cure for end-stage heart disease.
Recipients must take immunosuppressive medication for life and be monitored for infection, rejection, and graft arteriopathy. However, these results are impressive considering that the recipient population today is considerably sicker than earlier allograft candidates. In light of these findings, few would deny cardiac allotransplantation its present claim to "success.
First, for Barnard and co-workers what can we presume as "success" warranting advancement to the clinical arena? They performed the first human adult cardiac allotransplantation when the maximum survival in immunosuppressed adult dogs had been days average survival days 11 and suggested that "against the background of this research.
Indeed, in their report of this case, they further described the scientific basis of their clinical advancement by explaining that "this achievement did not come as a surprise to the medical world.
Steady progress toward this goal had been made by immunologists, biochemists, surgeons, and specialists in other branches of medical science all over the world during the past decades to ensure that this, the ultimate in cardiac surgery, would be a success" 7. Although we may, in retrospect, consider them justified in their declaration, in fact, at that time the endeavor was highly controversial and came as a surprise to much of the medical world.
Second, under what conditions did they proceed with this clinical trial? Given the "hope of success," Barnard and colleagues selected a patient "considered to have heart disease of such severity that no method of therapy short of cardiac transplantation could succeed" 7. The patient, a year-old man, had remained in intractable congestive heart failure following multiple myocardial infarctions despite all medical management Finally, in this clinical arena, what defined for Barnard and colleagues "success" warranting further investigation?
Further editorials regarding the ethics of cardiac transplantation viewed the procedure as a legitimate experiment but not a treatment 15 , while in , the American College of Cardiology suggested with regard to the "success" of allotransplantation that results varied: ". Indeed, "success" did vary along a spectrum of results.
Barnard and colleagues' first allotransplant recipient lived for 18 days and ultimately died of pneumonia. However, their second recipient, 1 month later, survived more than 19 months before dying of chronic rejection Their third patient also lived more than 20 months after allotransplantation and ultimately died of carcinoma of the stomach without signs of acute or chronic rejection One can only speculate how different the world reception to allotransplantation would have been had the latter two patients represented the first and second recipients of cardiac allotransplants.
Would these survival data be considered "success," or would they still pale in comparison with the theoretical goal of obtaining a graft that could function normally indefinitely? Clinical cross-species transplantation dates to the early twentieth century, with kidney xenografts from rabbit, pig, goat, non-human primate and lamb donors After these early failures, the scientific literature was largely devoid of reports of clinical xenotransplantation for nearly 40 years.
In , Reemtsma and colleagues described six human recipients of chimpanzee kidneys, the longest survivor of whom died of causes unrelated to rejection 9 months after xenotransplantation The first cardiac xenotransplantation, performed by Hardy in , also represented the first attempt at cardiac transplantation in humans, predating Barnard's report by nearly 4 years 1.
Since , when Hardy and colleagues at the University of Mississippi performed the world's first heart xenotransplant using a chimpanzee as a donor, there have been eight documented attempts at clinical heart xeno-transplantation. Five of these donors were non-human primates 2 baboons, 3 chimpanzees and three were domesticated farm animals 1 sheep, 2 pigs 21 - The longest survivor was a newborn infant with hypoplastic left heart syndrome.
However, by the time the first human neonatal cardiac xenotransplantation was performed by Bailey in the so-called "Baby Fae" case , there had been only limited experimental experience with prolonged graft survival in the newborn xenotransplant recipient.
Studies presented by Bailey and co-workers shortly before the Baby Fae case described a mean survival time of 72 days in newborn lamb-to-goat xenotransplants, with one survivor living to days This advancement of xenotransplantation into the clinical forum was met with resistance in the medical community because of a perception that research with acceptable survival "success" had not been achieved experimentally.
As Losman in an editorial regarding the Baby Fae experience stated, "It appears that this baboon-to-infant transplantation did not rest on such a [scientific] basis [as did Barnard's earlier operation in ] " During the past 3 years, investigators at the University of Pittsburgh reported two cases in which they transplanted a baboon liver into a human recipient, obtaining a day survival in their first reported case, and a day survival in the second 29 ; J.
Fung, pers. The investigators' overwhelming effort to prevent rejection led them to use a harsh immunosuppressive regimen that permitted multiple life-threatening infections.
Rejection was not the major clinical obstacle they encountered; therefore, they recommended a more directed and less arduous immunosuppressive regimen for future patients. More alarming have been the attempts to apply xenotransplantation of distantly related species to the clinical arena. In , both Cooley and Ross transplanted sheep and pig hearts, respectively, into dying human recipients 30 , Both grafts failed upon reperfusion, presumably because of hyperacute rejection.
More recently, Czaplicki and co-workers in described a case in which they attempted the xenotransplantation of a pig heart into a human recipient with Marfan's syndrome By their report, no evidence of hyperacute rejection was present at the time of death nearly 24 hours after xenotransplantation. Their protocol used an unusual immunosuppressive regimen in which both donor and recipient received, in addition to conventional immunosuppression, both thymic tissue extracts and fetal calf sera.
This regimen also included the extracorporeal perfusion of two pig hearts with the recipient's blood in an attempt to remove human anti-pig antibodies before the orthotopic transplantation of the functional pig heart As astonishing as this case may be in its extension to the clinical arena of a technique not yet shown to be effective in the experimental laboratory, it is not unique.
Also in , Makowka and colleagues transplanted a pig liver into a year-old woman dying of acute liver failure from autoimmune hepatitis pers. Despite the fact that, at present, it appears unlikely that sufficient "success" has been achieved in the laboratory regarding xenotransplantation between distantly related species to warrant advancement to the clinical arena, these investigators were able to obtain approval from their hospital's ethics committee and institutional review board to proceed with the clinical trial.
Most experts in the field of xenotransplantation share the opinion that pig-to-human organ transplantation remains at least 3 to 5 years from clinical trials. Considerable advances in the field of cardiac xenotransplantation have subsequently emerged worldwide since Hardy's first clinical attempt in , with a better understanding of the xenorejection process and a more sophisticated insight into mechanisms for its control. Extended graft survival has been achieved in a number of different experimental models, including a greater than tenfold graft survival in non-human primates treated with conventional cyclosporine-based immunosuppression 34 , 35 a more than thirtyfold increase in survival over controls described by Celli and colleagues in a rodent model 36 , and survival beyond 1 year reported by Kawauchi and colleagues in a non-human primate model These findings support the potential for achieving clinically relevant graft survival in humans.
The question is whether we have reached a stage in laboratory experimentation to justify further attempts at advancing cardiac xenotransplantation to the clinical arena. If we view the current status of experimental accomplishments in xenotransplantation with the same scrutiny as that of allotransplantation at the time of Barnard's endeavor, we are left with similar conclusions; first, comparable graft survival time has been achieved in animal models of xenotransplantation as was evident for allotransplantation before Second, with our current understanding of cardiac allotransplantation has also come a greater awareness of its limitations.
Thus, the conditions for the advancement of xenotransplantation arguably could be fulfilled by a patient with end-stage heart disease who is a candidate for allotransplantation, but for whom a donor cannot be identified in time.
Finally, the clinical "success" of xenotransplantation might also be considered as was the case for allotransplantation any graft survival, and the goal of xenotransplantation to strive for extended graft survival. However, political and scientific sensibilities today clearly differ from those of the s, and so the critical assessment of xenotransplantation must be more rigorous than our previous discussion.
Indeed, the above comparison was put forth largely to underscore the more humble origins of the now successful therapy allotransplantation to which xenotransplantation is currently compared. What then defines "success" in the laboratory warranting advancement from the laboratory to the operating room?
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