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CLINICIANS AND RESEARCHERS AGREE THAT
ENABLING A TRANSPLANT RECIPIENT'S IMMUNE SYSTEM TO PERMANENTLY ACCEPT
A NEW ORGAN IS THE BIGGEST CHALLENGE FACING THE FIELD OF TRANSPLANTATION.
If only the recipient's immune system could be persuaded to accept
-- or "tolerate" -- the new tissue, lifelong reliance on anti-rejection
drugs could be avoided.
One key to achieving tolerance might lie in investigations
being carried out by pediatrics professor Alan Krensky, MD, on the
effects of the immune system's HLA molecules. Researchers in his
lab have found that small pieces of HLA molecules induce tolerance
in animal models. They are still figuring out exactly how these
small protein fragments work but Krensky believes that they somehow
block the proliferation of T cells that accompanies an escalation
of the immune response.
Samuel Strober, MD, professor of medicine (immunology
and rheumatology) is taking another tack to induce tolerance. He's
using transplanted immune cells from the kidney donor's bone marrow
to prime the recipient's immune system to accept the kidney as its
own. First, Strober uses radiation and treatment with an anti-T-cell
antibody to temporarily deplete the recipient's immune system of
T cells. Then, when the immune cells from the donor are introduced,
the new cells can establish themselves in the recipient's tissues
without hindrance and co-exist peacefully with the recipient's own
cells. A patient he previously transplanted using this protocol
has done without immune suppression drugs for 15 years. Strober
is currently refining the method and plans to recruit patients for
a new trial to test modifications to the procedure.
C. Garrison Fathman, MD, professor of medicine (immunology
and rheumatology), is also focusing on short-term treatments to
induce tolerance in transplant patients. He is experimenting with
immune system molecules found naturally within the body, such as
cytokines, to quickly restore balance to the immune system.
Living with intolerance
To help a patient survive an acute rejection -- the
body's immediate reaction to a transplant -- clinicians need to
act fast. But currently, the only way to conclusively diagnose acute
rejection is by directly sampling some of the kidney tissue via
a biopsy, an invasive procedure. Assistant professor of pediatrics
Minnie Sarwal, MD, PhD, hopes that a molecule called granulysin,
released by T cells as they begin to multiply, might prove to be
a more accurate indicator of rejection than is the commonly used
marker creatinine.
Surgery professor Randall Morris, MD, focuses his
research specifically on chronic rejection -- the slow form of rejection
that can destroy a transplant over a period of months or years.
Immunosup-pressive drugs like cyclosporine are usually effective
at treating acute rejection but doctors have had less success preventing
or treating chronic rejection. Morris has found that a drug called
rapamycin seems to prevent the scarring inside blood vessels that
is a hallmark of chronic rejection. "The results are exciting because
they lay a solid foundation for clinical trials of rapamycin for
the prevention and treatment of chronic rejection in patients with
organ transplants," says Morris.
Since achieving tolerance is not yet an option for
most transplant patients, they must rely on continual treatment
with immunosuppressive drugs, most of which have undesirable side
effects. Some Stanford researchers, including Sarwal and surgery
professor Oscar Salvatierra, MD, are investigating less debilitating
long-term immunosuppressive regimens. In particular, they are developing
a treatment that avoids the use of steroids, which are among the
most common immunosuppression drugs used. While steroids are very
effective, they can cause side effects including hypertension, facial
disfigurement and bone deterioration, Salvatiera notes. So far,
all of the children adhering to the steroid-free protocol retain
a healthy kidney a year after their transplant operation. -- KW
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