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Researchers at SFVAMC hope their results will lead to an earlier,
more sensitive, and more accurate standard test for chronic lung rejection.
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Researchers at the San Francisco VA Medical Center (SFVAMC)
and the University of California, San Francisco (UCSF) have
identified six genes associated with lymphocytic bronchitis,
which is thought to lead to obliterative bronchitis (OB),
the most common cause of long-term failure of transplanted
lungs.
The researchers hope their results will lead to an earlier, more
sensitive, and more accurate standard test for chronic lung
rejection, as well as greater understanding of the rejection
process.
The study is being published in the September 2005 issue of the
Journal of Heart and Lung Transplantation, currently available
online.
In obliterative bronchitis, scar tissue forms in breathing
passages of the transplanted lung, narrowing them and eventually
making it impossible for the recipient to breathe. The exact cause
is unknown, but it is believed to be related to rejection of the
lung by the recipient's body.
"For lung transplant patients, the biggest barrier to long-term
survival is control of rejection," says principal investigator
George Caughey, MD, head of Pulmonary and Critical Care Medicine at
SFVAMC. "If we know rejection is occurring, we can adjust the
patient's medication to try and prevent it. But the problem with
lung transplants is that it's hard to detect chronic rejection."
Currently, he says, OB is best detected through a breathing
test--but by the time the disease has a perceptible impact on the
patient's ability to breathe, it's often too late to treat
effectively.
Caughey and his fellow researchers studied lung biopsy samples
from 22 lung transplant patients, with the goal of detecting genes
and gene products associated with inflammation and formation of scar
tissue in breathing passages. Using a customized version of a
conventional laboratory technique, they found that they were able to
look at hundreds of gene products simultaneously in lung tissue
samples only a few millimeters across. "That was our first
achievement: being able to accurately measure that many genes in
small samples," notes Caughey, who is also a professor of medicine
at UCSF. "We succeeded way beyond our expectations."
The researchers then correlated the genetic test results with
results from microscopic pathology examinations, tissue cultures,
X-rays, CT scans, and breathing tests in each patient. They
identified six genes that correlate with lymphocytic bronchitis,
potentially opening the way to a genetic test that would identify OB
before it manifests. "The beauty of this approach is that it could
be applied in a regular laboratory," Caughey says.
However, he cautions, "we need to validate this data in a larger,
separate set of patients to prove that these biomarker genes
actually work. And we're testing that now." Currently, Caughey's
research team is studying biopsy samples from more than 100 UCSF
lung transplant patients, who regularly undergo biopsies as part of
standard follow-up care.
Another potential benefit of the research, predicts Caughey, will
be a better understanding of lung rejection at the genetic level. In
turn, he believes, this could lead to the development of medications
that directly target genes responsible for the scarring process in
the lung, instead of anti-rejection drugs that broadly compromise
the immune system, which are the major tools currently available to
fight lung rejection.
Co-authors of the study were Xiang Xu, MD, PhD, Jeffrey A.
Golden, MD, Gregory Dolganov, PhD, Kirk D. Jones, MD, Samantha
Donnelly, PhD, and Timothy Weaver, Bsc, all of UCSF.
###
The research is funded by a grant from the National Institutes of
Health that is administered jointly by the Northern California
Institute for Research and Education (NCIRE) and UCSF's
Cardiovascular Research Institute, and is supported by the Diamond
Family Foundation.
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