Lung transplants – a treatment of last resort for end-stage lung disease – have given thousands of patients a second lease on life. But the long-term success of the procedure still lags far behind that seen in heart, liver and kidney transplants, and scientists have struggled to understand why.
With a new $7.3 million grant from the National Institutes of Health (NIH), lung transplant surgeons and researchers at Washington University School of Medicine in St. Louis are investigating the immunological basis of lung transplant rejection, with the aim of improving the long-term outlook for patients.
“The lower success rates of lung transplants remain a major problem,” said principal investigator Daniel Kreisel, MD, PhD, a Washington University lung transplant surgeon at Barnes-Jewish Hospital. “Unlike other organs, lungs are constantly exposed to whatever is in the environment – bacteria, viruses and air pollution, for example – and we think this increases the risk of chronic rejection and, eventually, failure of the organ.”
Five years after lung transplantation, about half of the lungs are still functioning, according to the U.S. Organ Procurement and Transplantation Network. This compares with five-year organ survival rates of about 70 percent for heart, liver and kidney transplants. The poorer outcomes after lung transplants are closely linked to their higher rejection rates.
After organ transplants, patients routinely receive anti-rejection drugs. The drugs stop the immune system from attacking newly implanted hearts, livers, kidneys or lungs but also leave patients susceptible to infections. Further, earlier research by the Washington University team indicates that broadly dampening the immune response – long considered crucial to transplant success – inadvertently may encourage lung transplant rejection.
The new funding will support three projects over a five-year span that investigate different immunological aspects of lung transplant tolerance, or the ability of the immune system to recognize a transplanted lung as the body’s own.
One project, led by Kreisel, a professor of surgery, will study the link between tolerance and the development of new lymphoid tissue within newly transplanted lungs. In other types of organ transplants, such tissues appear to be linked to poor outcomes. But in the lungs, their appearance may be critical to a good outcome.
A second project, led by lung transplant surgeon A. Sasha Krupnick, MD, associate professor of surgery, builds on the team’s earlier work in mice, showing that newly transplanted lungs are more likely to be rejected if key immune cells are missing.
These so-called memory T cells regularly patrol the lungs to distinguish between harmless challenges and serious insults, such as respiratory viruses or pathogenic bacteria. Without these cells, the immune system recognizes a transplanted lung as harmful and mounts and attack that eventually can lead to rejection of the organ.
“The anti-rejection drug regimens that we use for lung transplants were adopted based on their effectiveness in other types of organ transplants, with little understanding or appreciation that lungs seem to have their own unique immunological milieu,” Krupnick said.
A third project, led by Andrew Gelman, PhD, associate professor of surgery, looks at the role of infection-fighting immune cells called neutrophils in building tolerance. The presence of neutrophils is important for jump-starting memory T cells soon after a transplant, and they also play a role in preventing lung infections that can develop after a transplant. But under certain circumstances, the same cells have been linked to rejection. The new work focuses on elucidating the cells’ opposing roles.
“Taken together, our studies will provide critical new insights into the immunological underpinnings of transplant tolerance and rejection,” Gelman said. “It is our hope that new discoveries will set the stage for developing novel therapeutic strategies to improve the success of lung transplants.”
A microsurgical core will be led by Wenjun Li, MD, assistant professor of surgery, who has helped develop several of the experimental procedures that will be employed in the research.