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Beeckmans, H.* ; Kerckhof, P.* ; Geudens, V.* ; Vanluyten, C.* ; Zapata-Ortega, M.* ; Willems, L.* ; Van Herck, A.* ; Vermaut, A.* ; Aerts, G.* ; Hooft, C.* ; Jin, X.* ; Van Slambrouck, J.* ; Zajacova, A.* ; Mercurio, M.* ; Cortesi, E.* ; Mohamady, Y.* ; Tielemans, B.* ; Knoop, C.* ; Janssens, W.* ; Gayan-Ramirez, G.* ; Wuyts, W.A.* ; Godinas, L.* ; Bos, S.* ; Wauters, E.* ; Dupont, L.J.* ; Van Raemdonck, D.* ; Weynand, B.* ; Saez-Gimenez, B.* ; Schiller, H.B. ; Schupp, J.C.* ; Kneidinger, N.* ; De Sadeleer, L.J.* ; Ahangari, F.* ; McDonough, J.E.* ; Ceulemans, L.J.* ; Yildirim, A.O.* ; Kaminski, N.* ; Vanaudenaerde, B.M.* ; Vos, R.*

A transcriptomic atlas of chronic lung allograft dysfunction.

Eur. Respir. J. 68:2502380 (2026)
DOI PMC
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 intrapatient 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, which 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Antibody-mediated Rejection; Hyperlipidemia; Phenotypes
ISSN (print) / ISBN 0903-1936
e-ISSN 1399-3003
Journal European Respiratory Journal
Quellenangaben Volume: 68, Issue: 4, Pages: , Article Number: 2502380 Supplement: ,
Publisher European Respiratory Society
Publishing Place Sheffield
Reviewing status Peer reviewed
Institute(s) Research Unit Precision Regenerative Medicine (PRM)
Grants Belgian Foundation Against Cancer (mandate for basic and clinical oncology research)
Transplant Fellowship from the European Society of Organ Transplantation