Proteins May Predict Lung
Transplant Rejection
FORT LAUDERDALE, FL (Nov. 3, 2006) _ Using the
latest in high tech tools, researchers have identified three proteins
that were highly predictive of chronic lung rejection up to 20 months
before the rejection occurred.
Lung transplant patients have the highest mortality
rate of organ recipients, about 45% over five years, said lead
investigator and pulmonologist Chris Wendt. Currently, there is no
reliable way to predict which transplants will fail, and when signs of
chronic rejection appear, it is usually too late to reverse it, she
said. If doctors can predict which patients are beginning to reject the
transplanted organ, they could try to head it off, she said.
The study, “Proteomic biomarkers of chronic lung
allograft rejection,” was carried out by Wendt, Tereza Cervenka,
Madelaine Haddican, Yan Zhang and Gary Nelsestuen, of the University of
Minnesota, Minneapolis. The researchers will present the study during a
poster session at the upcoming conference, “Physiological Genomics
and Proteomics of Lung Disease,” in Fort Lauderdale, Nov. 2-5.
The American Physiological Society is presenting the conference.
The researchers used the power of computers and
new, sophisticated methods of analysis to find the proteins that form a
“biosignature” or “biomarker” of organ rejection from among the
thousands of proteins that exist in the lung.
Disease disturbs
protein function
Lung transplants are a common therapy for many
end-stage lung diseases such as chronic obstructive pulmonary disease,
cystic fibrosis, pulmonary hypertension, idiopathic pulmonary fibrosis
and other diseases.
Patients who receive a new lung may suffer bouts of
acute or chronic rejection. Acute rejection often responds to therapy.
Chronic rejection, which results in scarring of the lung’s airways
following inflammation, is irreversible. In addition, often by the time
doctors make the diagnosis, the disease
is already fairly advanced, Wendt said.
“We want to identify people at risk of chronic
rejection before they have the clinical manifestations,” Wendt said. In
addition to early identification, the researchers hope to eventually
open the door to developing a preventative treatment and also gain
insight into the physiological mechanisms of lung rejection.
Lung fluid samples
from ’93-‘96
The study used 411 lavage samples obtained from 137
lung transplant recipients from 1993-1996, Wendt explained. A lavage is
a liquid that doctors introduce into the lung to wash out unwanted
material. When the wash is removed, it contains biological material,
including proteins, that the researchers hypothesized would be able to
identify those who later suffered organ rejection.
Because this study looked back at patients treated
years ago, the researchers could look for differences between patients
who subsequently suffered chronic lung rejection and those who did not.
The researchers combined proteomics (the study of
proteins), the latest in mass spectrometry technology and the best
analytical methods from the field of bioinformatics (the use of
computers and statistics to analyze and find patterns in scads of data).
They hypothesized that proteins would change as chronic lung rejection
developed and that the new technology would make it possible to find
these patterns from among the thousands of proteins at work in the
lungs.
Some promising results
An earlier study from the laboratory had found that
elevated levels of human neutrophil peptide (HNP), declining Clara cell
secretory protein and some previously unidentified proteins were highly
correlated with chronic lung rejection. In particular, the researchers
found that HNP was three times more likely to be elevated among those
who later suffered chronic rejection.
Later analyses identified 265 proteins that were
upregulated in lung rejection up to 20 months before it happened. With
yet more research, they found the following became elevated with chronic
rejection:
“Preliminary evidence suggests these biomarkers
will be an early sign of lung transplant rejection,” the authors wrote.
The research is continuing to determine which protein combinations are
the best predictors and whether some biomarkers may be better than
others at different points of the disease’s development.
The information could offer inroads to new
therapies, said Wendt. Doctors may be able to increase the dose of
anti-rejection drugs when the early markers of rejection appear. Or,
they may reduce anti-rejection drugs for people who do not show early
signs of rejection. (Anti-rejection drugs have their own side effects,
including an increased chance of developing kidney disease or
malignancies.)
Finally, these findings could be used to understand
the physiological mechanisms that lead to lung rejection, Wendt
explained. Her team has developed two mouse models to determine whether
these proteins play a role in the development of chronic lung rejection
or whether they are a byproduct of the disease.
* * *
The
American Physiological Society was founded in 1887 to foster basic and
applied bioscience. The Bethesda, Maryland-based society has 10,500
members and publishes 14 peer-reviewed journals containing almost 4,000
articles annually.
APS provides a wide range of research, educational
and career support and programming to further the contributions of
physiology to understanding the mechanisms of diseased and healthy
states. In 2004, APS received the
Presidential Award for Excellence in Science, Mathematics and
Engineering Mentoring.
