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Promise of xenotransplants tempered by viruses.

Human xenotransplantation trials could begin in 5 years, thanks to advances in immunosuppression and the creation of miniature swine whose organs do not provoke hyperacute rejection, experts say.

But even as researchers overcome the hurdle of immune response, they must tangle with another potential problem: infectious diseases that could be transmitted via the xenograft or evolve within the recipient as the disparate tissues commingle.

Nearly 83,000 patients are on the United Network for Organ Sharing (UNOS) waiting lists each year, and more than 6,000 die before an organ becomes available.

"Those numbers include only those who are healthy enough to get on the waiting list. If you're too old or have other illnesses, you aren't even considered for a transplant," said David Sachs, M.D., director of the Transplantation Biology Research Center at Massachusetts General Hospital, Boston. Less than half of those eligible to donate organs at their death become donors. And UNOS says that even if all eligible donors became actual donors, demand would still exceed supply.

Xenografting could provide a way for patients to receive a replacement organ before their health critically deteriorates. Animal organs would be free of human pathogens that sometimes hitchhike on allografts and immune to human pathogens that sometimes destroy them.

Pigs are the ideal source of xenografts, Dr. Sachs said, because they reproduce quickly, they have been used as food animals for thousands of years, and the organs of the adult miniature swine are equivalent in size to those of an adult human.

The porcine xenograft concept is not new; pig heart valves have been used for years, Pig-to-human islet cell transplants have already undergone clinical trials, and a few Parkinson's patients have received brain grafts of fetal pig neural tissue. But whole pig organs have never been introduced into a human because, until recently, primate studies have been unsuccessful.

Taming Rejection in the Lab

A new strain of genetically modified pigs lacks the [alpha]Gal 1 epitope, the primary cause of an intense, almost immediate rejection syndrome that has stymied primate trials. Dr. Sachs has established a line of these pigs at his lab.

He transplanted hearts from the Galknockout pigs into eight baboons. The hearts were heterotropic--not intended to sustain life--and attached to the baboons' abdominal aorta and inferior vena cava. Three baboons died quickly from other problems, but while the grafted hearts were still beating. In the remaining animals, the grafts continued to function for 59-179 days. "The one that beat for 6 months is the longest graft survival ever recorded for any pig organ in a nonhuman primate," Dr. Sachs said (Nat. Med. 2005;11:29-31).

He also transplanted pig kidneys into 11 baboons; these were intended as orthotopic, life-sustaining grafts. Most of the grafts survived more than 30 days--the previous survival limit for a pig kidney graft in a primate--and two survived more than 80 days (Nat. Med. 2005;11:32-3). All of the kidney procedures also included transplantation of thymic tissue from the donor pig. The baboon received a vascularized thymic lobe graft before the kidney graft. All the baboons were thymectomized, splenectomized, and T-cell depleted before their transplant.

The protocol relies on the transplanted thymus to self-regulate T-cell activity, allowing tapering of drug therapy beginning on day 30. Dr. Sachs wasn't able to completely taper any of the pigs, but the protocol has important implications for human trials, he said.

"The idea with the thymus transplant is the same as with a bone marrow transplant--to eliminate those new T cells that can react against both self- and pig tissue, and leave all the other T cells that react against microbes intact," he explained.

If it can be refined for human trials, thymic tolerance induction might allow immunosuppressive drugs to be kept at a level that sustains the graft while minimizing the recipient's risks.

One Hurdle Down, One to Go

Immune response has long been the focus of xenotransplant research. More recently, however, the possibility of infectious disease has grabbed scientists' attention. Jay A. Fishman, M.D., of the Transplant Infectious Disease and Compromised Host Program at Massachusetts General Hospital, was among the first to broach the issue.

"When I first raised that question in the xenotransplantation community 10 years ago, I got blank looks," he said. "We had no evidence there were any potential risk factors associated with xenotransplantation. Then we cloned the porcine endogenous retrovirus, and it was shown to be infective in in vitro human cell lines" (J. Virol. 1998;72:4503-7).

The porcine endogenous retrovirus (PERV) isn't the only potentially dangerous microbe that pigs carry, but it poses a particular risk: It may be a permanent fixture of pig tissue. Like many retroviruses, it's encoded in the host's germline and passed on through succeeding generations.

None of the PERV viruses cause infections in pigs, but no one knows if they could behave differently in humans--or even if they can live in humans. Although two types of PERV do infect human cells in vitro, they've never shown up in vivo.

"We don't have any evidence this will happen." Dr. Fishman said. "There have been a number of studies of people who were exposed to living pig tissue, and none of them have evidence of PERV in the blood" (Science 1999;285:1236-41).

Dr. Fishman's lab has developed diagnostic assays, not only for PERV but for many other infective agents known to exist in the donor herd. Other assays exist in veterinary medicine. They will probably all be used to monitor the health of any human xenograft recipients. But it's not the known agents that worry Robin Weiss, Ph.D.--it's the unknowns.

"Virologists have discovered six or seven new kinds of pig virus in the last 10 years, so there's no reason to think we've discovered the last one," said Dr. Weiss, a virologist at University College London, in an interview. "We would have no way to test for any unknown viruses [in a xenograft recipient]--you can't test for something that hasn't been discovered," he said. In 1997, his laboratory discovered the three infectious strains of PERV--two of which can infect human cells in culture (Nat. Med. 1997;3:282-6).

Only as research progresses will any as-yet undescribed agents come to light--perhaps making their debut as diseasecausing organisms in xenograft recipients.

The risk could extend far beyond a single patient. It's not impossible to envision a pig virus that evolves human-to-human transmissibility within a xenograft, or a pig-human recombinant virus.

"There are two levels of risk to be analyzed. If I were told there was a 1% chance I could get infected from a pig transplant, that would probably be an acceptable risk for me if I would be dead without the organ. But if I were told there was a 1% chance that I could be the index case for a worldwide epidemic of a new disease, I might decide otherwise," Dr. Weiss said.

Although he believes the possibility of an unknown virus that jumps species or a new recombinant virus that emerges in xenotransplant patients is remote, he also urges extreme caution in eventual human trials, with mandatory lifelong monitoring of recipients and their intimate contacts.

What Privacy?

The U.S. Department of Health and Human Services has already broached the idea of monitoring in its draft document, "Informed Consent in Clinical Research Involving Xenotransplantation." Written by the Secretary's Advisory Committee on Xenotransplantation, the document outlines how informed consent should be structured for patients who enroll in any trials, including explanations of potential personal and public health risks and post-transplant monitoring (

It would be essential, the document says, for xenotransplantation research participants to understand that lifelong surveillance is critical, and that failure to comply could, in some cases, force legal action. "There is no legal precedent for requiring monitoring of intimate contacts, however, and the document relies on personal responsibility to fill that gap. That might be a gamble, Dr. Weiss said. "We know from HIV, a disease with known transmissibility and devastating consequences, that relying on people to behave responsibly hasn't worked well at all."


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Author:Sullivan, Michele G.
Publication:Internal Medicine News
Geographic Code:1USA
Date:Nov 1, 2005
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