Researchers identify genes associated with lung transplant rejection

Could mean new test, treatments

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.