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New clues found in cause of early lung transplant failure

Treatments targeting specific recipient and host immune cells may prevent a deadly condition following lung transplantation

Among organ transplant patients, those receiving new lungs face one of the highest rates of organ failure and death compared with people undergoing heart, kidney and liver transplants. One of the culprits is inflammation that damages the newly transplanted lung.

Now, scientists at Northwestern Medicine and Washington University School of Medicine have uncovered the precise cells that flow into and harm the lung soon after a transplant. The resulting dysfunction is the leading cause of early death after lung transplantation and contributes to organ rejection that can lead to death months or years later.

The study, which included animal models and human subjects, may lead to drug therapies that target the destructive cells.

“This study is a fundamental advancement in our understanding of early lung injury after transplantation,” said co-senior author Dr. Ankit Bharat, the Harold & Margaret Method Professor of Surgery at Northwestern University Feinberg School of Medicine and surgical director of Northwestern Medicine lung transplantation. “We are very excited because the findings build on our past research, which demonstrate the complex, yet fascinating, interaction between the host’s immune cells and the freshly transplanted lung. It also introduces clinically relevant therapies which may extend the lives of lung transplant patients.”

The study was published online May 21 in The Journal of Clinical Investigation.

“More than 50 percent of lung transplant patients experience some lung damage after a transplant,” said co-senior author Dr. Daniel Kreisel, professor of surgery and of immunology and pathology at Washington University and surgical director of lung transplantation at Barnes-Jewish Hospital. “Eliminating this problem would increase the success of lung transplants.” 

Early lung damage typically occurs in the 72 hours following surgery. When a lung is removed from a donor, it is flushed with a cold preservation fluid and placed on ice, where it is deprived of blood and oxygen. The damage typically occurs after the lung is surgically implanted and the recipient’s blood enters the lung for the first time. The recipient’s white blood cells seep into the transplanted lung and trigger inflammation that harms the organ’s tissue. Affected patients can require extended time on a ventilator in the hospital or even extracorporeal life support to give the new lung a chance to recover.

The condition is a big reason the success of lung transplants trails other solid organ transplants. Five years after lung transplantation, about half of the transplanted 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 to 80 percent for liver, heart and kidney transplants.

Studying mice that had undergone lung transplants, the researchers found that monocytes are rapidly released from the spleen after lung transplantation. These cells infiltrate the newly transplanted lung and then produce a protein called interleukin 1 beta, which, in turn, invites in the tissue-damaging white blood cells known as neutrophils.

“Now that we know what leads to the early injury following lung transplantation, we can start working on developing treatments to target this,” Bharat said. “For example, using drugs that have already received FDA-approval to inhibit interleukin 1 beta for other inflammatory conditions can be potentially used for this purpose.”

Researchers at the University of Virginia, Charlottesville, also contributed to the study.

This research was supported by National Institutes of Health (NIH) grants 1P01AI116501, R01 HL094601, T32DK077662, P01AG049665, P01HL071643 and HL125940; Veterans Administration Merit Review grant 1l01BX002730; Department of the Army grant W81XWH-15-1-0215; The Foundation for Barnes-Jewish Hospital; the International Society of Heart and Lung Transplantation Research Awards; the Thoracic Surgery Foundation; the American Lung Association; and the Society of University Surgeons. The Northwestern University Flow Cytometry Core Facility was supported by the National Cancer Institute of the NIH grant CA060553. The Flow Cytometry Cell Sorting system at Northwestern was purchased with support from NIH grants 1S10OD011996-01, R01HL125655 and R01HL131908.