Overview
In the first three days after a lung transplant, some recipients develop a severe form of lung injury called primary graft dysfunction, or PGD. It is the most common cause of death in the period right after surgery, and there is no drug that treats it directly.
The injury has an unusual cause. A donor lung spends time without a blood supply between being removed and being connected to the recipient. When blood flow is restored, the sudden return of oxygen to tissue that has been without it sets off inflammation, and that inflammation damages the thin barrier separating the air spaces from the blood vessels. Fluid leaks across that barrier, and the lung struggles to move oxygen into the body.
Our research asks which parts of the immune system drive this, on the reasoning that a specific cause is something a specific drug could target. We found that a type of white blood cell called a natural killer cell is a driver of the injury rather than a bystander, and we have since traced how those cells are switched on, how they reach the lung, and which patients are most vulnerable.
Natural killer cells and NKG2D
Natural killer cells are part of the innate immune system, the fast branch that recognizes damaged and infected cells without needing prior exposure to them. They carry a surface sensor called NKG2D, which detects molecules that stressed or injured cells display on their outside. We established that activation through NKG2D is a mechanism of the injury that follows restored blood flow, working across experimental models and human transplant samples.
Genetic evidence
Human genetics strengthened that finding. MICB is one of the molecules NKG2D recognizes. A common inherited difference in the MICB gene was associated with acute lung injury and death across multiple groups of patients. Because a person's genetics are fixed before any transplant occurs, an association of this kind argues that the pathway contributes to the injury rather than simply appearing alongside it.
How the cells reach the lung
Later work traced how natural killer cells arrive in the injured lung, identifying a role for a surface receptor called CCR5 in that movement. That mechanism has since informed a clinical strategy aimed at reducing early graft injury by blocking the same pathway.
Linking early injury to later decline
We have also connected early injury to long-term outcome. Telomeres are protective caps on the ends of chromosomes that shorten each time a cell divides, and short telomeres indicate cells with limited remaining capacity to renew themselves. Short telomeres in airway cells were associated with both primary graft dysfunction and chronic dysfunction years later, which suggests that how well the airway can repair itself shapes what an early injury eventually becomes.
Work with other centers
We contribute to the Lung Transplant Outcomes Group, a cohort spanning many transplant programs, which makes it possible to test how PGD is defined, how often it occurs, and how treatment patterns have changed across a large population rather than at one hospital.