New Research Shows Molecular Basis for Chronic Rejection in Lung Transplantation Via The Airway Transcriptome

In lung transplantation, chronic rejection, or chronic lung allograft dysfunction (CLAD), remains a common occurrence and one of the biggest challenges to successful long-term outcomes. Chronic rejection of lung allografts is the biggest driver of patients exhibiting a poor mean survival rate of just under six years after transplantation.

“Chronic rejection is the Achille’s heel of lung transplantation; it is the major barrier to long-term survival in our patients," says John F. McDyer, MD, Professor of Medicine in the Division of Pulmonary, Allergy and Critical Care Medicine, and Director of the Lung Transplant Translational Research Program at UPMC. “Even our current testing options — through bronchoscopy — yields few visible cases or evidence of rejection as seen at the tissue level. We need to develop better molecular diagnostics to identify and predict in whom CLAD will strike. Novel and predictive biomarkers that can detect the development or presence of chronic dysfunction early, or that can potentially be targeted with therapeutic options, are desperately needed if we hope to improve long-term survival outcomes.”

In a new study published in June in the American Journal of Transplantation, Dr. McDyer and colleagues analyzed tissue samples from the small airways in a cohort of lung transplant patients at UPMC exhibiting chronic lung allograft dysfunction.

The investigators used a novel fine nylon transbronchial brush to sample tissues from the small airways in the lungs of the patients. Dr. McDyer’s team then subjected the samples to RNA sequence analysis in order to investigate and characterize the airway transcriptome for identifiable markers of dysfunction.

Dr. McDyer’s team found that in lung transplant patients with chronic lung allograft dysfunction, their airway samples proved to have a messenger RNA signature that distinguished them from stable lung transplant patients. The genes in the transcriptomic signature were dominated by those known to be responsible for a Type-1 immune response, which is the dominant type of response to, among other things, viral infection. Furthermore, the analysis showed that several immune-regulatory products — indoleamine 2, 3 dioxygenase 1 (IDO-1), and the tumor necrosis factor superfamily 6B (TNFRSF6B) were highly upregulated in the tissue samples.

As part of the analysis, Dr. McDyer's team sent what they identified as their transcriptome signature to colleagues at the University of California, San Francisco, for further analysis and corroboration in their patients with chronic lung rejection in whom they conducted a recent study using airway brush collections in lung transplant patients experiencing rejection. The results aligned, and the finding of this signature in the airway transcriptome can now be applied to a larger study, currently in the planning phases and led by Dr. McDyer and his colleagues at the University of Pittsburgh and UPMC.

Clinical Implications

Dr. McDyer and colleagues’ study is a major advancement in the potential development of new testing modalities and therapeutic development targets to better characterize, diagnose, and treat or prevent CLAD. 

“This approach has the potential to significantly impact the diagnosis and early intervention in CLAD patients. It may also lead to new pathways targeting the upregulated mechanisms in lungs experiencing the Type-1 inflammatory response that Dr. McDyer’s team uncovered in their analysis.

Multicenter Study to Launch and Investigate Airway Transcriptome Signature

Dr. McDyer and colleagues are planning a new multicenter study they hope to launch in 2022, examining the airway transcriptome signatures collected from CLAD patients in a study funded by the Cystic Fibrosis Foundation. The study will recruit patients from at least 12 centers across the United States to build the evidence base for using the airway transcriptome signature that Dr. McDyer and colleagues have discovered to assess CLAD in transplant patients.

Dr. McDyer and his colleagues at the University of Pittsburgh and UPMC also are participating in a multicenter, National Institutes of Health-funded trial called  "Long-Term Follow Up of the LTOG Cohort" clinical trial. This trial involves both prospective and retrospective studies of long-term CLAD in lung transplant patients to develop phenotypes of the disorder.

References

Iasella CJ, Hoji A, Popescu I, Wei J, Snyder ME, Zhang Y, Xu W, Iouchmanov V, Koshy R, Brown M, Fung M, Langelier C, Lendermon EA, Dugger D, Shah R, Lee J, Johnson B, Golden J, Leard LE, Ellen Kleinhenz M, Kilaru S, Hays SR, Singer JP, Sanchez PG, Morrell MR, Pilewski JM, Greenland JR, Chen K, McDyer JF. Type-1 Immunity and Endogenous Immune Regulators Predominate in the Airway Transcriptome During Chronic Lung Allograft Dysfunction. Am J Transplant. 2021 Jun; 21(6): 2145-2160. 

Learn more about Dr. McDyer and his research program.