Proteins May Predict Lung Transplant Rejection

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:

• matrix metalloprotein-9 (66 times more likely to suffer rejection)
• proteinase 3 (nine times more likely)

"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.