More than half of lung-transplant recipients experience rejection of their new lungs within five years, a complication that has long puzzled doctors. A recent study from Northwestern Medicine sheds light on the reasons behind this problem and offers potential pathways for new treatments.
Researchers found that after a lung transplant and in chronic disease states, abnormal cells appear and communicate in ways that cause ongoing lung damage and rejection. The findings could help develop new drugs not only for transplant rejection but also for other diseases involving lung scarring, such as COPD and COVID-19-related damage.
“Chronic lung-transplant rejection has been a ‘black box.’ We knew it happened but did not exactly know why,” said Dr. Ankit Bharat, professor of thoracic surgery at Northwestern University Feinberg School of Medicine and executive director of the Northwestern Medicine Canning Thoracic Institute. “Our study provides the first comprehensive cellular and molecular roadmap of the disease.”
The study was published on October 22 in JCI Insight.
Chronic lung allograft dysfunction (CLAD), which includes various forms of chronic rejection, is the leading cause of death after the first year following transplantation. Currently, there are no effective treatments for CLAD once it develops; re-transplantation is often the only option.
By examining nearly 1.6 million cells, scientists were able to distinguish between abnormal cells from donor lungs and those from the recipient’s immune system. They discovered harmful interactions between these cell types that drive ongoing damage. This understanding may lead to new drug targets and could benefit patients with several kinds of lung-scarring diseases.
The team identified a specific rogue cell type (KRT17 and KRT5 cells) involved in scarring across multiple diseases, including idiopathic pulmonary fibrosis, interstitial lung disease, COPD, COVID-19-related lung damage, and transplant rejection. By integrating data from different scarring conditions, they created a detailed reference map showing both shared features among these diseases and characteristics unique to each one.
“By comparing chronic rejection to other scarring lung diseases, we identified both shared and unique features,” said Bharat. “This means treatments developed for one condition might help others. The benefits extend far beyond transplant patients.”
Other discoveries include previously unrecognized cell populations in rejected lungs: “exhausted” T cells—immune cells that remain activated but do not function properly—and “super-activated” macrophages—cells that promote inflammation and scarring.
Researchers also developed computational methods to combine data from multiple studies, overcoming technical challenges that had limited previous research efforts.
The team pinpointed genes and signaling pathways such as PDGF, GDF15, and TWEAK that are involved in scarring processes. Existing medications like nintedanib (marketed as Ofev or Vargatef) and pirfenidone (Esbriet), currently approved for other lung diseases, might be repurposed for treating transplant rejection.
“The findings have immediate translational potential,” Bharat said. “We’re already exploring therapeutic strategies based on these discoveries.”
While focused on CLAD, the research has broader implications for understanding pulmonary fibrosis—a group of disorders affecting hundreds of thousands of patients—not just those who have undergone transplants.
“The molecular pathways and cell types we identified are relevant to conditions affecting hundreds of thousands of patients with various lung-scarring diseases, not just transplant recipients,” Bharat said. “This work essentially provides a ‘Rosetta Stone’ for understanding lung scarring regardless of the initial trigger.”
The study included contributions from Dr. Yuanqing Yan, Taisuke Kaihou, Emilia Lecuona, Xin Wu, Masahiko Shigemura, Haiying Sun, Chitaru Kurihara, Ruli Gao, Felix L Nunez and G.R. Scott Budinger at Northwestern University. Funding was provided by several grants from the National Institutes of Health.