STANFORD, Calif. — People with organ transplants, resigned to a
lifetime of anti-rejection drugs, may now have reason to hope for a
respite, say researchers at Lucile Packard Children’s Hospital and the Stanford University School of Medicine.
Using a simple blood sample, the scientists have identified for the
first time a pattern of gene expression shared by a small group of
patients who beat the odds and remained healthy for years without
medication.
The findings suggest that transplant
recipients who share the same pattern of genes but are still on
conventional medication may be able to reduce or eliminate their
lifelong dependence on immunosuppressive drugs. The study may also help
physicians determine how best to induce acceptance, or tolerance, of
donor organs in all transplant patients, regardless of their gene
expression profiles.
“We’re very excited by the findings,” said Minnie Sarwal,
MD, PhD, a pediatric nephrologist at Packard Children’s. “Most
transplant patients who stop taking their medications will reject their
organ. But now we have the chance of telling someone committed to a
lifetime of drugs that it may be possible to minimize their exposure to
the drugs.”
Although the anti-rejection medications, known
as immunosuppressants, tamp down the immune system enough to permit
lifesaving organ transplants, their benefits come at a price. They also
quash the body’s natural response to dangerous invaders, such as
bacteria and viruses, and to rogue cancer cells. Transplant physicians
prescribing immunosuppressants to their patients walk a fine line
between avoiding organ rejection and increasing the risk of infection
and cancer.
Sarwal, associate professor of pediatrics at the medical school, is the
senior author of the research, published Aug. 20 in the advance online
edition of the Proceedings of the National Academy of Sciences. She collaborated with physicians at Stanford and Packard Children’s, as well as with colleagues from the Veterans Affairs Palo Alto Health Care System and several institutions in France, China and the Netherlands.
The researchers used microarray, or gene chip, technology to compare
gene expression patterns in blood samples from 16 healthy volunteers
with those from three groups of adult kidney transplant recipients from
the United States, Canada and France: 22 people on anti-rejection
medications who had healthy donor kidneys, 36 people who were taking
their medications but who were still rejecting their organs and 17
“tolerant” people who had successfully stopped taking their medications
without rejecting their donated kidneys.
Sarwal and her collaborators found that the expression pattern of just
33 genes in a random sampling of peripheral blood could be used to
accurately pick out more than 90 percent of the tolerant patients.
What’s more, one out of 12 stable, fully medicated patients and five
out of 10 patients on a modified, low-dose immunosuppressant regimen
shared very similar expression patterns.
The findings imply that patients regularly taking immunosuppressants
who have a strong matching pattern for the tolerance genes may be able
to safely reduce or even eliminate their dependence on the medication.
Equally important, it suggests that patients who don’t share the gene
pattern, even if on very low-dose medication, should be particularly
vigilant about continuing to take their immunosuppressants.
“For the first time, we now have evidence that will help us say to the
five out of 10 patients without this expression pattern, ‘Please,
please don’t think about changing your medications’,” said Sarwal. “At
the same time, we may be able to say a different patient, ‘We’d like to
try to cut back your drugs.’”
Although it’s not known exactly how the 33 genes identified by the
researchers affect the development of tolerance, the expression and
function of nearly one-third are controlled by a regulatory molecule
called TGFbeta. Sarwal and her colleague speculate that the genes
somehow affect the development of immune cells responsible for
distinguishing self from non-self. But they caution that even long-term
tolerance may not last forever; immune challenges such as severe
infection can sometimes cause rejection of a donated organ years after
anti-rejection medication was successfully stopped.
“The real value of this technology is the ability to easily and
repeatedly monitor patients over long periods of time,” said Sarwal.
“We can keep an eye on this genetic signature and watch for changes
that might indicate the beginning of rejection before any clinical
signs are apparent. This could be a very exciting advance for both
patients and physicians as it can lead to the ability to, for the first
time, safely customize immunosuppression for an individual patient.”
Sarwal’s Stanford and Packard colleagues include biostatistician Li Li,
MD; research scientist Szu-chuan Hsieh, MS; postdoctoral scholar Meixia
Zhang, PhD, and Oscar Salvatierra, MD, PhD, professor of surgery and of
pediatrics, emeritus. Other co-authors are at the Institut National de
la Santé et de la Recherche Médicale in France, China Medical
University and other institutions.
