What question did this study set out to answer?

This research aims to identify molecular signatures associated with chronic lung allograft dysfunction and its severity.

July 4, 2026

A Transcriptomic Atlas of Chronic Lung Allograft Dysfunction

Key Points

This research aims to identify molecular signatures associated with chronic lung allograft dysfunction and its severity.
Performed high-resolution imaging-based gene expression profiling of 128 lung samples from CLAD and donor lungs.
Utilized weighted gene co-expression network analysis and validated findings across four datasets.
Identified a hub gene-panel with robust diagnostic performance for CLAD discrimination.
Unsupervised clustering identified two transcriptomic endotypes: mild-fibrotic and advanced-fibrotic.
Five molecular programmes were found, indicating various disease mechanisms and potential drug targets.
A 26-gene hub panel demonstrated strong diagnostic capability to differentiate CLAD.

Abstract

Background Chronic lung allograft dysfunction (CLAD) is the leading cause of late mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are the main underlying clinical entities. Their molecular and cellular signatures are unclear and, therefore, we aimed to identify molecular programmes associated with morphological disease severity in CLAD. Methods We performed high-resolution imaging-based gene expression profiling of 128 lung samples from explanted CLAD and donor lungs, using weighted gene co-expression network analysis, cellular and pathway enrichment, and hub gene identification. Findings were validated across four datasets, including a murine transplant model, human BOS lungs, transbronchial biopsies, and bronchoalveolar lavage fluid of lung transplant recipients. Results Unsupervised clustering revealed two transcriptomic CLAD endotypes aligning with mild-fibrotic (BOS, mild RAS) and advanced-fibrotic disease (moderate/severe RAS). Samples from the same patient often diverged molecularly, underscoring intra-patient heterogeneity and limitations of current phenotypical classification. Five molecular programmes emerged: (1) epithelial stress and innate immunity in early-fibrotic CLAD, (2) progressive adaptive immunity and cytotoxicity in advanced CLAD, (3) transient extracellular matrix remodelling, (4) progressive endothelial loss/dysfunction, and (5) progressive loss of homeostasis, wherein multiple potential druggable targets were detected. Finally, we identified a 26 CLAD hub gene-panel, that showed robust diagnostic performance to discriminate CLAD. Conclusion CLAD is a spatially heterogeneous, yet molecularly continuous disease process, wherein BOS and RAS represent variable stages of a shared immunopathological continuum. Our findings support the development of lung-specific molecular classifiers to guide diagnostics and reveal novel targets for personalised therapies in transplantation.

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