(Circulation. 1998;97:1431-1432.)
© 1998 American Heart Association, Inc.
Xenotransplantation
Ruth SoRelle
The support and
opposition to xenotransplantation—the transplant of organs from one
species to another—are both based on truth.
It is true that there are far too few human organs available to be
transplanted into individuals who will likely die without such a
transfer. And it is true that the use of animal organs that have been
altered to overcome barriers presented by cross-species
rejection is an increasingly enticing solution to the shortage.
But it is also chillingly true that it is impossible to know what is
being transplanted along with such organs. The threat of an
as-yet-unknown disease making the cross-species jump with a heart,
liver, kidney, or other body part alarms experts such as Jonathan
Allan, a virologist at the Southwest Foundation for Biomedical
Research. In particular, he said, it is difficult to test for the
presence of a virus if you do not know it exists. The threat that a new
epidemic could spring from such transplants is alarmingly real, said
Allan in an interview last fall.
Yet it appears the US Food and Drug Administration, Centers for Disease
Control and Prevention, and other federal agencies are ready to issue
guidelines that would allow trials of xenotransplants to
begin—again.
In truth, xenotransplants have a long history in modern medicine. In
early 1964, Keith Reemtsma, MD, of Tulane University oversaw
xenotransplantation of kidneys from chimpanzees into six patients, one
of whom lived 9 months after the transplant. Other transplants
followed, including those by transplant veteran Thomas Starzl, MD,
at the University of Pittsburgh. The results, however, were
disappointing, and the field fell into disfavor until 1985, when
surgeon Leonard Bailey, MD, startled the world by implanting a
baboon's heart into an infant known as Baby Fae, who had been born
with hypoplastic left heart syndrome. He had hoped that the child's
undeveloped immune system would not readily reject the organ, and the
child did live for 4 weeks after the transplant. In the early 1990s,
Starzl transplanted baboon livers into two patients with advanced
hepatitis B. One patient lived 70 days; the other, 26. Both died of
infection because of the large doses of immunosuppressive drugs needed
to prevent rejection of the primate organ.
In recent years, basic research has led the way to uncovering methods
that will prevent the hyperacute immune response that dooms most
xenotransplants. Abdul Rao, MD, director of the Section of Cell
Transplantation at the University of Pittsburgh, said complement in the
circulation is key to this hyperacute response. In our bodies,
complement binds to any cell that has a receptor for it. But right next
to the complement binding sites are complement
inactivators, which stop the action of the chemical.
If a pig organ is transplanted into a human, it binds human complement,
which is then activated. "But the pig complement
inhibitory protein cannot stop the complement," said Dr
Rao. "The human complement gets activated and eventually
results in hyperacute rejection."
But there is another level of complexity to the problem, he said. "We
humans, because of exposure to a lot of microbial antigens in our
lives, have antibodies against what is known as a galactose
(1-3)-galactose terminal sugar residue," he said. These antibodies
mean that there is such sugar residue, known as Gal for short, in the
human system.
"In pigs, on the contrary, the protein is present, but the
antibody is not. If you put a pig organ in a human, the antibodies
against cells in the pig organ are already present. These
carbohydrates are everywhere in the organ. The graft is destroyed
within minutes," Dr Rao said.
"How can you prevent this? You endow the pig with human
inhibitory protein. This has been achieved by transgenic
technology," he said. Both Imutran, a biotechnology company based in
the United Kingdom, and Nextran, a US company, have achieved this
goal.
Drs Rao and Starzl are collaborating with Nextran on research using
transgenic pigs with the transgenic inhibitory protein. In
fact, Dr Rao said, there are three transgenic inhibitory
proteins in the pigs. "If one misses at one stage of complement
activation, another catches," Dr Rao said. "It is more likely to
prevent hyperacute rejections. Or we hope it will be. Once the
hyperacute barrier is taken care of, these organs become similar to a
baboon-to-human transplant. The major barrier is cell-mediated
rejection."
Other investigators have attempted to deplete the store of Gal
antibodies before transplant by filtering the blood through an external
pig organ, which sops up the antibodies. The blood is then returned to
the body. However, such depletion is cumbersome and temporary. An
alternate pathway can sometimes allow complement destruction to proceed
even without antibodies.
In an attempt to block the action of complement proteins, Fred
Sanfillipo, MD, of the Johns Hopkins University of School of Medicine
in Baltimore, Md, flooded the blood of monkeys with soluble proteins
that bind to the complement proteins. Primates treated in this way
survived as long as 6 weeks with pig hearts in place. Untreated monkeys
reject pig hearts in fewer than 8 days.
There are ethical and scientific questions about the prospect of
modifying donor pigs, said Dr Rao. "These pigs have humanized
inhibitory proteins. Any ethical committee would refuse to
modify a nonhuman primate to make it more human. What, then, is the
barrier to creating a superhuman?"
But Dr Rao's contention that pigs can be bred virtually "virus
free" is being questioned because of findings of
endogenous retroviruses in the genomes of even the cleanest
pigs. In a commentary in the journal Nature, Robin Weiss of
the Institute of Cancer Research in London wrote,
"Xenotransplantation will potentiate the risk of pig-to-human
transfer of viruses not transmitted by the respiratory route. First,
the physical barrier is broken by transplanting living porcine tissue
organs into humans. Second, the immunosuppression required to prevent
xenograft rejection may allow zoonotic viruses to adapt to human
infections. Third, the genetic modification of pigs may allow
preadaptation of animal viruses for human infection."
(Nature. 1998;391:327–328.)
As a microbiologist, Weiss warned that there is a risk of setting off a
new human epidemic; he pointed out that HIV-1 probably began by
cross-species transfer and that HIV-2 almost certainly did. "We need
a Hippocratic ethic for community and public health at least to do no
harm," he said.
Weiss advised caution, neither prohibiting xenotransplant into humans
nor rushing headlong into the procedure. An editorial in the same issue
of Nature (1998;391:309) called for a moratorium on
xenotransplants until international debate on the pluses and minuses
has taken place. A host of scientists signed on the moratorium
bandwagon in commentary published in Nature Medicine
(1998;4:141–144).
Guidelines proposed by the FDA that would allow xenotransplant trials
to proceed cover everything from the makeup of the transplant team to
plans for health surveillance of both animals and human. There are
requirements for consent forms, animal procurement, animal screening,
and health maintenance of the animals. The guidelines also call
for archiving records of both animals and human patients as well as
banks of stored serum and tissue samples from each. If a problem
arises, the archives will make it possible to identify and contact
xenotransplant recipients for testing and alert them to possible health
risks.
These guidelines, proposed in the summer of 1996, are still pending.
Final rules are expected sometime this year. Yet, as Mary Pender, FDA
deputy commissioner, said at a recent meeting of an agency committee
studying xenotransplants, the issue has not been easy. "As is
painfully evident from the porcine endogenous retrovirus
issue you are going to discuss today, the science of
xenotransplantation is still evolving, and there is much we do not know
about the risks from transplantation, thereby making the creating of a
regulatory system different. As usual, there are some who would prefer
to have the agency leave their xenotransplantation efforts alone.
However, the field will not stand still as we wonder what to do, and we
believe that the public will be disadvantaged if we do nothing."
Circulation Newswriter
