A Transcriptomic Atlas of Chronic Lung Allograft Dysfunction.
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Beeckmans Hanne, Kerckhof Pieterjan, Geudens Vincent, Van Luyten Cedric, Zapata-Ortega Marta, Willems Lynn, Van Herck Anke, Vermaut Astrid, Aerts Gitte, Hooft Charlotte, Jin Xin, Van Slambrouck Jan, Zajacova Andrea, Mercurio Martina, Cortesi Emanuela, Mohamady Yousry, Tielemans Birger, Knoop Christiane, Janssens Wim, Gayan-Ramirez Ghislaine, Wuyts Wim A, Godinas Laurent, Bos Saskia, Wauters Els, Dupont Lieven J, Van Raemdonck Dirk, Weynand Birgit, Saez-Gimenez Berta, Schiller Herbert B, Schupp Jonas C, Kneidinger Nikolaus, De Sadeleer Laurens J, Ahangari Farida, McDonough John E, Ceulemans Laurens J, Yildirim Ali Ö, Kaminski Naftali, Vanaudenaerde Bart M, Vos Robin
Аннотация
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.