Winter 2006

Genes Related to Lung Transplant Rejection Identified

Researchers at UCSF and the San Francisco Veterans Affairs Medical Center (SFVAMC) have identified six genes associated with lymphocytic bronchitis, which is thought to lead to obliterative bronchiolitis (OB), the most common cause of long-term failure of transplanted lungs.

The study was conducted at UCSF Medical Center by George Caughey, M.D., Jeffrey Golden, M.D., and their colleagues. 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.

"For lung transplant patients, the biggest barrier to long-term survival is control of rejection," says Caughey, the study's principal investigator, who last year became 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."

Matching Genes to Disease

Currently, Caughey 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 Golden 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, the 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.,/p>

Another potential benefit of the research will be a better understanding of lung rejection at the genetic level, Caughey and Golden say. In turn, they believe, this could lead to the development of medications that directly target genes responsible for the scarring process in the lung, instead of using anti-rejection drugs that broadly compromise the immune system, and that are the major tools currently available to fight lung rejection.

"This type of bedside-to-bench research will help physicians tailor antirejection immunosuppressive therapy to match the degree to which rejection-related genes are activated," says Golden. "In the absence of such sophisticated markers, we are forced to use a 'one-size-fits-all' approach that produces a possibly too-potent regimen."

The study was published in the August 2005 issue of the Journal of Heart and Lung Transplantation. In addition to Golden and Caughey, co-authors of the study were Xiang Xu, M.D., Ph.D; Gregory Dolganov, M.D., Ph.D; Kirk D. Jones, M.D.; Samantha Donnelly, Ph.D; and Timothy Weaver, B.Sc; 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.

To contact Dr. Jeffrey Golden, call (415) 353-2935. To contact Dr. George Caughey, call (415) 221-4810, ext. 2385.

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