Organ transplant patients routinely take medications that suppress their immune systems to keep their bodies from attacking new hearts, livers, kidneys, or lungs. But research with mice suggests that after lung transplants the drugs may do more harm than good.
Researchers found mice were more likely to reject newly transplanted lungs if key immune cells were missing, a situation that simulates what happens when patients take immunosuppressive drugs.
These “memory T cells” are primed to “remember” pathogens that infiltrate the body and quickly trigger an immune response during subsequent encounters.
In heart, liver, and kidney transplants, knocking down memory T cells with immunosuppressive drugs helps to ensure that the immune system recognizes a new organ as the body’s own. But not so in lung transplants.
“In mice, memory T cells are critical for a lung transplant to have a good outcome,” says co-corresponding author Daniel Kreisel, a Washington University in St. Louis lung transplant surgeon at Barnes-Jewish Hospital. “A lot of transplant recipients receive drugs that indiscriminately deplete many different T cells. But in lung transplants, this strategy may contribute to organ rejection.”
In light of the new findings, researchers think current immune-suppression strategies should be re-evaluated in lung transplantation.
“Most immunosuppressive drugs were adopted for use in lung transplants based on their results in other solid organ transplants, without an appreciation that the lung is different,” Kreisel says.
‘Lungs are unique’
The research also may help explain, in part, why the success of lung transplants in people lags far behind other solid organ transplants.
Five years after lung transplantation, fewer than half are still functioning, according to the US Organ Procurement and Transplantation Network. This compares with five-year organ survival rates of about 70 percent for heart, kidney, and liver transplants.
The poorer outcomes after lung transplantation are related largely to higher rejection rates, the researchers say. About 1,800 lung transplants are performed each year in the United States.
“The high failure rate of lung transplants is a major problem,” says co-corresponding author Alexander Krupnick, a Washington University lung transplant surgeon at Barnes-Jewish Hospital.
“Lungs are unique. Unlike other organs, they are continually exposed to bacteria, viruses, and everything else in the environment, and we think this increases the risk of chronic rejection and the eventual failure of the organ.”
Memory T cells regularly patrol the lungs, where they distinguish harmless challenges like cat dander or tree pollen from more serious insults like respiratory viruses or pathogenic bacteria. Without these cells, the immune system recognizes a newly transplanted lung as harmful and mounts an attack that eventually can lead to rejection of the organ.
An aggressive attack
As part of the study, the researchers performed lung transplants in mice. When memory T cells were absent in these mice, the newly transplanted lungs underwent rejection. The researchers found evidence of severe inflammation in the lungs, an indicator that the immune system had instigated an aggressive attack against the foreign organ.
However, when the scientists infused memory T cells into the lung recipients, they could reduce inflammation and prevent rejection. Further, they defined the molecular pathway by which memory T cells naturally dampen the body’s response to lung transplants.
Rather than attacking the lungs, memory T cells unleash a cascade of signaling molecules that encourage the immune system to see the transplanted lung as the body’s own.
Based on their findings, published in the Journal of Clinical Investigation, the researchers say they want to find ways to selectively target immunosuppression in lung transplants, to encourage memory T cells to thrive while eliminating other T cells that harm transplanted lungs.
“We really need to develop immune suppression strategies just for lung transplants that boost the ability of memory T cells to do their job,” Krupnick says. “This may give newly transplanted lungs a much better chance of surviving long after the transplant is over.”
The American Association for Thoracic Surgery, the Thoracic Surgery Foundation for Research and Education, the American Thoracic Society Lungevity Foundation Research Grant, the American Cancer Society, the Foundation for Barnes-Jewish Hospital, and the International Society for Heart and Lung Transplantation funded the research.