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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa

      Background

      Many lung transplants fail due to chronic lung allograft dysfunction (CLAD). We recently showed that transbronchial biopsies (TBBs) from CLAD patients manifest severe parenchymal injury and dedifferentiation, distinct from time-dependent changes. The present study explored time-selective and CLAD-selective transcripts in mucosal biopsies from the third bronchial bifurcation (3BMBs), compared to those in TBBs.

      Methods

      We used genome-wide microarray measurements in 324 3BMBs to identify CLAD-selective changes as well as time-dependent changes and develop a CLAD classifier. CLAD-selective transcripts were identified with linear models for microarray data (limma) and were used to build an ensemble of 12 classifiers to predict CLAD. Hazard models and random forests were then used to predict the risk of graft loss using the CLAD classifier, transcript sets associated with rejection, injury, and time.

      Results

      T cell-mediated rejection and donor-specific antibody were increased in CLAD 3BMBs but most had no rejection. Like TBBs, 3BMBs showed a time-dependent increase in transcripts expressed in inflammatory cells that was not associated with CLAD or survival. Also like TBBs, the CLAD-selective transcripts in 3BMBs reflected severe parenchymal injury and dedifferentiation, not inflammation or rejection. While 3BMBs and TBBs did not overlap in their top 20 CLAD-selective transcripts, many CLAD-selective transcripts were significantly increased in both for example LOXL1, an enzyme controlling matrix remodeling. In Cox models for one-year survival, the 3BMB CLAD-selective transcripts and CLAD classifier predicted graft loss and correlated with CLAD stage. Many 3BMB CLAD-selective transcripts were also increased by injury in kidney transplants and correlated with decreased kidney survival, including LOXL1.

      Conclusions

      Mucosal and transbronchial biopsies from CLAD patients reveal a diffuse molecular injury and dedifferentiation state that impacts prognosis and correlates with the physiologic disturbances. CLAD state in lung transplants shares features with failing kidney transplants, indicating elements shared by the injury responses of distressed organs.

      KEYWORDS

      Abbreviations:

      CLAD (chronic lung allograft dysfunction), TBB (transbronchial biopsy), 3BMB (third bronchial bifurcation mucosal biopsy), BOS (bronchiolitis obliterans syndrome), RAS (restrictive allograft syndrome), RATs (rejection-associated transcripts), IGTs (immunoglobulin transcripts), MMDx (Molecular Microscope Diagnostic System), TxBx (time of biopsy post-transplant), PBTs (pathogenesis-based transcript sets), AUC (area under the curve), TCMR (T cell-mediated rejection), DSA (donor-specific antibody), IRITD3 (Injury-repair induced transcripts day 3), IRITD5 (Injury-repair induced transcripts day 5), QCATs (Cytotoxic CD8 T cell-associated transcripts), MANOVA (type II multivariate analysis of variance), GSEA (gene set enrichment analysis)
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