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Xenotransplantation - Closing in on the Clinic

David K.C. Cooper, MD, PhD

A. Joseph Tector, MD, PhD
University of Alabama Birmingham
Birmginham, AL, USA

We are all aware of the continuing critical shortage of organs from deceased donors for clinical transplantation. Whatever attempts are made to increase human organ donation, it seems very unlikely the demand will ever be satisfied. The transplantation of organs from pigs could resolve this problem, and for more than 30 years, efforts have been made to investigate the pathobiological barriers that need to be overcome.

In recent years, relatively rapid progress has been made, largely due to improved methods of generating genetically-engineered pigs and the introduction of novel immunosuppressive agents, e.g., costimulation blockade agents. Life-supporting pig kidney transplantation in nonhuman primates is now associated with excellent graft function for many months, or even more than a year, in the absence of features such as proteinuria.

A major step has been the ability to generate pigs that express none of the three known antigens against which humans have natural antibodies, so-called triple-knockout [TKO] pigs (Only two need to be knocked out for pig organ transplantation into nonhuman primates, as one of these glycans is shared with the pig). Experimental studies are now being directed towards determining whether conventional (i.e., calcineurin-based) immunosuppressive therapy is adequate to prevent a T cell-induced elicited antibody response against a TKO pig organ, which was not successful when the pig organ expressed these antigens.

Extensive testing of the sera from patients on the waiting list for a kidney transplant indicate that approximately one-third of them demonstrate no antibody binding to TKO pig cells, suggesting there should be no risk of rejection if the T cell response can be adequately suppressed. Furthermore, by no means all anti-HLA antibodies cross-react with swine leukocyte antigens (SLA), thus enabling some HLA-sensitized patients to receive a pig graft without added risk. It therefore seems timely to consider approaching the FDA with a view to initiate a limited clinical trial of pig kidney transplantation.

The careful selection of patients for the first trial will be important. There is clear evidence that older patients, e.g., >60 years of age, are disadvantaged and often wait many years for a suitable allograft to become available, particularly if the patient has any degree of sensitization to HLA. Indeed, many of these patients are never offered a suitable allograft during the years before they die. If these patients could be offered a period of time (perhaps months or years, but as yet undetermined) of good quality life, free from the restrictions of dialysis, a pig kidney transplant might prove welcome and well worthwhile.

Why should the first trial be of pig kidney transplantation, and why not one of the other vital organs? Although the results of heterotopic heart transplantation in nonhuman primates are good, there remain problems in achieving prolonged survival after orthotropic heart transplantation that need to be resolved, and the results of transplantation of pig livers and lungs remain significantly inferior to that of kidneys.

It is uncertain what requirements will be requested by the FDA, but under the biosecure isolation conditions under which the source-pigs will be bred and housed, the risk of a pig infectious microorganism being transferred to the patient is small - significantly less than the risk of transfer of a virus, e.g., CMV, EBV following allotransplantation. Furthermore, there has been no in vivo evidence suggesting that porcine endogenous retroviruses will be problematic, which can in any case be treated by the several anti-retroviral agents now available.

The time is approaching when a clinical trial can be fully justified - indeed it could be considered unethical not to offer a pig kidney to a patient who in all likelihood is condemned to spend the rest of his or her life on dialysis. The hope is that this first small trial will open the way for all patients awaiting an organ transplant (and many others with conditions such as diabetes mellitus and Parkinson's disease) to be treated in a timely manner.

"History tells us that procedures
that were inconceivable yesterday,
and are barely achievable today,
often become routine tomorrow."

- Thomas E. Starzl, 1982. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.

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