Overview
Chronic lung allograft dysfunction, or CLAD, is a lasting loss of function in a transplanted lung. It affects roughly half of recipients within five years and remains the main limit on how long a transplanted lung lasts. At present the only definitive treatment is another transplant.
It is diagnosed when a recipient's breathing test falls by at least a fifth from their own best level after transplant and stays down. It takes two main forms. In one, the smallest airways narrow and scar until air can no longer pass through them easily. In the other, the lung tissue itself and its lining stiffen with scar tissue. Both involve damage that does not reverse.
The central difficulty is timing. By the time the decline is obvious on a breathing test, a great deal of airway damage has usually already happened, and the biology that might have responded to treatment may no longer be active. Much of our work is therefore aimed at finding the process earlier, while it can still be changed, and at understanding what makes an injured airway heal properly in one person and scar in another.
Detecting it earlier
We developed methods that measure molecular activity directly in the transplanted airway, using cells collected by brushing the lining of the small airways, rather than inferring it from lung function. Across several centers, gene activity measured this way was associated with CLAD before it became clinically apparent, and with mortality risk. More recent work has described airway molecular signatures associated with antibody-mediated rejection, a form of rejection driven by antibodies against the donor lung.
The airway lining
We study the layer of cells lining the airway as an active participant in the shift from acute injury to chronic dysfunction, not merely as a target of immune attack. Several processes have emerged from this work: inflammatory signaling that keeps immune activity going, killing activity by immune cells, responses to low oxygen, damage-response pathways inside the cells themselves, and changes to the growth and repair machinery of the lining cells. That last finding provides the biological rationale for clinical evaluation of inhaled sirolimus, a drug that acts on exactly that machinery, in early CLAD.
Biological aging
We examine biological aging in both the donor lung and the recipient. Two people of the same age can have cells of very different biological age, and we measure this through telomere length and through chemical marks on DNA that accumulate over a lifetime. Short telomeres in the donor lung and in the airway have been associated with worse outcomes, including primary graft dysfunction and shorter time free of CLAD. Taken together with the epithelial work, these findings broaden chronic rejection beyond a model centered on immune cells alone, and suggest that lasting changes in the airway lining and in biological aging influence whether an injured airway repairs normally or stays vulnerable.