[Frontiers in Bioscience 1, d248-265, September 1, 1996]
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CAVEAT LECTOR



XENOTRANSPLANTATION - STATE OF THE ART

D.K.C. Cooper, MA, PhD, MD, MS, FRCS, FACC, FACS

Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

Received 07/16/96; Accepted 08/12/96; On-line 09/01/96

6. DISCUSSION

Methods that allow successful discordant xenotransplantation will clearly open up new areas of surgical therapy. Patients with native organ failure who are in need of a transplant will be able to undergo the procedure electively or immediately the need arises. They will no longer be condemned to wait anxiously in precarious health for weeks, months or even years before ultimately undergoing transplantation as an emergency procedure at a less-than-optimal time of the day or night. Patients with borderline contraindications to allotransplantation will be given the opportunity of xenotransplantation as there will no longer be a restriction on the number of donor organs. Transplantation will become a common procedure in countries such as Japan where to-date the absence of brain death laws has prevented allografting except from living-related donors. Diabetic patients may receive pig pancreatic islet cell transplants (108), negating the need for daily porcine insulin injections. The ethical problem of whether retransplantation should be offered to a patient will be overcome by the abundance of donor organs.

There will therefore be a great expansion in organ transplantation worldwide (4) and it is likely that both patients and physicians will not wish to persist with inadequate medical therapy, including dialysis, if successful organ xenotransplantation is readily available.

Will the public accept an organ from a pig? (109). Pig heart valves have been utilized for many years and have become acceptable to the public in general, including those of the Jewish and Muslim faiths. Porcine insulin is used in millions of diabetics worldwide. The results of a survey carried out in the USA in 1993 indicated that 84% of those questioned would accept an allograft if they needed one and no fewer than 51% would accept a xenograft if no allograft was available (110). As the people surveyed were presumably healthy individuals who did not anticipate the need for transplantation even in the remote future, the 51% acceptance rate for a xenograft was surprisingly high. It is likely that if the survey had been confined to patients awaiting an organ transplant, particularly those on life-support in an intensive care unit, then the percentage who would have accepted a xenograft would have been very much higher.

In an interesting editorial, Chen and Michler (111) discussed the difficult question of when to initiate a clinical heart xenotransplantation program. They suggested (quoting the work of Fox and Swazey (112)), that three questions need to be answered, namely "(i) in the laboratory, what defines success of a sufficient level to warrant advancement to the clinical arena? (ii) under what clinical condition should this advancement proceed? and (iii) in the clinical arena, what defines success of a sufficient level to warrant further evaluation?" They do not provide conclusive answers to these questions but clearly believe that "the question that currently remains is not how, but rather when should heart xenotransplantation advance to the clinical arena."

Which of the methods and approaches briefly outlined in this review is most likely to be successful in allowing clinical organ xenotransplantation? The answer is probably a combination of techniques and/or agents, as is the case with allotransplantation today. It is unlikely that one single approach will be entirely successful. Those with insight in this respect should be encouraged to heed the words of William Shakespeare: -

"If you can look into the seeds of time,
And say which grain will grow and which will not,
Then speak to me."
(Macbeth)

Accepting the difficulty of predicting the future, it would seem that xenotransplantation offers us the first real opportunity for modifying the donor as opposed to the recipient. This opens up great possibilities, particularly in this era of rapidly developing techniques such as genetic engineering and gene transfer. The breeding of a pig with a vascular endothelial structure against which humans have no pre-formed antibodies (and are unlikely to develop new antibodies) will be a major advance, and seems possible in the near future. Similarly, the ability of the pig organ to block the destructive effect of human complement will help overcome HAR. If neither of these techniques alone, or in combination, is entirely successful in preventing antibody-mediated rejection, then the inhibition of known anti-alphaGal antibodies by the infusion of an alphaGal oligosaccharide may lead to accommodation.

Even when we have successfully overcome the antibody-mediated complement-dependent HAR and the antibody-dependent delayed vascular rejection, we will almost certainly face further problems from a cellular response, which is likely to be severe (113,114). However, several novel pharmacologic immunosuppressive agents are currently being evaluated that lend hope that this hurdle will also be successfully overcome (43-51). Looking even further into the future, it is hoped that immunological donor-specific tolerance can be achieved in the human host to transplanted pig organs, thus negating the need for long-term immunosuppressive therapy and minimizing the late complications of such therapy.

There will remain, however, several unknowns. Will the porcine organ function satisfactorily in the human environment? (109,115). Pig hearts have functioned successfully in the heterotopic position in nonhuman primates for several weeks (18,101), as have pig kidneys (56). It is likely that both of these organs will fulfill the functions required of them in the human host. It is much less likely that a transplanted pig liver will fulfill all of the roles expected of it. Will pig proteins, enzymes, and hormones carry out their tasks in the human? (115). It is inconceivable that the products of a pig liver will be completely interchangeable with those of a human liver, but here again, in time, genetic engineering of the donor pig may allow some of these functions to occur satisfactorily.

We already have clinical evidence, however, that ex vivo perfusion of pig livers by blood from human patients in fulminant hepatic failure can lead to some improvement in cerebral activity, and therefore at least temporary support by a pig liver is likely to be beneficial (116,117). One area of interest and speculation is, of course, that after orthotopic transplantation using a pig liver, the liver will produce pig complement. This should help to protect the transplanted organ from HAR, but what effect it will have on the remaining human organs in the body and on the body's defense mechanisms to infection remains unknown.

There are those with a cynical outlook who for many years have predicted that "the future of transplantation is xenotransplantation, and always will be!". Unfortunately, to-date they have been proved correct! In the final decade of this century, however, we at last appear to be making some real progress, and there are glimpses of light at the end of the tunnel of ignorance and failure. I prefer, therefore, the much more positive attitude of George Bernard Shaw's character in "Back to Methuselah" who says:

"You see things: and you say 'why?'
Always 'why?'
But I dream things that never were:
And I say 'why not?'"

Nevertheless, there will undoubtedly be many pitfalls and disappointments ahead. The future has probably best been summed up by Professor Roy Calne, the pioneering transplant surgeon, who recently stated: "Clinical xenotransplantation is just around the corner, but unfortunately it may be a very long corner."

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