Author: Neighborhood Reporter
Author Date: 3/10/2003

Doctors at the University of Nebraska claim their transplant trials
with animals are paving the way to growing organs for human
transplantation someday, with fewer bouts of organ rejection. Their
study is published in the Feb issue of the journal Annals of Surgery.
(1)

Retraining the Immune System
The researchers manipulated the genetic makeup of a pigs heart to
see if they could control immune rejection after it was transferred
to a sheep. "The clinical use of pig organ xenografts is currently
precluded by severe acute rejection, which resists standard immune
suppression," they wrote.

Xenografts are portions of tissue transplanted from one species onto
or into individuals of non-similar species. Xenotransplantation is
the term typically used to describe the transplantation of animal
organs into humans.

Cellular Chimerism
William Beschorner, M.D, an adjunct professor of surgery at the
University of Nebraska and his colleagues theorized that using a
process known as cellular chimerism (kye-MEER-iz-um) might work in
xenotransplantation where other approaches have failed. In such
procedures, doctors must either use powerful immune-suppressing
drugs, which helps fight organ rejection but leaves the patient at
increased risk of infections, or implement immune tolerance and
tissue accommodation procedures after surgery, which might lead to
complications and frequent organ failure.

"Induction of cellular chimerism within the donor pigs, however,
could accomplish these goals before transplantation, significantly
reducing the risk," they wrote.

Beschorner and his fellow team of researchers grafted a pigs heart
into a sheep while successfully manipulating the immune systems of
both animals.

The doctors took bone marrow cells from the sheep and transferred
them to a pig fetus. After the pig was born, they took disease-
fighting white blood cells from the pigs spleen and transferred them
to the sheep. These cells contained genetic material from both
animals. The objective is to make two genetically different species
more similar so that when the transplant procedure takes place, the
risk of rejection is much lower.

When the swine matured, the researchers then grafted the pigs heart
onto the outside of the sheep, and connected blood vessels below the
sheeps neck. The sheep kept its own heart throughout the process.

As a comparison, the researchers also performed the pig-to-sheep
transplants in another group without also doing the cellular
manipulation.

They found that within four to eight days, all the organs
conventionally transplanted into sheep underwent acute rejection. By
contrast, only one rejection occurred out of 13 experimental
transplants. Immunosuppressant drugs like cyclosporine and
corticosteroids were used in all cases.

Human Transplant Implications
A trial using humans and pigs could work successfully in the same
way, with the pig fetus receiving human bone marrow cells, they
added. The technique, said Beschorner, could also work with other
organs like kidneys, livers and islet cells of the pancreas.

Pancreatic islet cells produce insulin in the body in response to a
drop in blood sugar levels.

"Our approach is to engraft cells from the patient within the donor
pig, and then we accomplish all the goals within the pig during
fetal development, and we can transfer those back into the patient
at a later time," Beschorner told Priority Healthcare.

The first goals is retraining the immune system to ignore the new
organ; one in which "the patient cells learn to recognize the pig as
itself, and therefore ignore it," said Beschorner, who is also
founder and president of Chimerics, Inc.

Tissue accommodation is another goal, in which tissue is "toughened
up", so that if the recipient generates antibodies, the tissue is
not injured. A third goal is developing pig organs that are more
humanlike, Beschorner explained.

"[Natural] pig livers probably would not provide really good, long-
term support for humans," Beschorner said. "But if we can make a
hybrid liver, which is part human liver cells, it would provide
better humanlike function."

For example, pig livers produce essential proteins necessary only in
pigs. If such a liver was transplanted into humans, the patient
would soon develop a protein deficiency because the new liver was
only producing pig-specific proteins. Developing a hybrid liver to
produce proteins necessary in humans would solve that problem.

This cellular transfusion is not a genetic transfusion, however.
Swine-specific cells still exist in these hybrid organs, possessing
their original genes. Human cells simply interact with the pig
cells, and become very tolerant to them, said Beschorner.

Instead of launching an immune attack against the new organ, the
recipients immune system will ignore it. "Were essentially re-
training the immune system so it will not reject the pig organ,"
Beschorner said.

No More Immunosuppressant Drugs?
Immune-suppressing drugs are still necessary in these transplants,
but not at the level used in human-to-human procedures. "There is
the potential that we could even decrease the amount of immune
suppression more, and possibly reach the point where we dont need
any," he said. "But thats a ways off."

Future Trials
The next step is to test the effectiveness of chimeric
transplantation between pigs and non-human primates, such as
baboons, Beschorner explained. "We need to be able to put a pig
liver into a baboon with modest immune suppression, and see it
survive for a prolonged period of time."