Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants

Abstract

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole‐genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response‐to‐wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response‐to‐wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased—dedifferentiation. Gene‐based classifiers predicted CLAD with AUC 0.70 (no time‐correction) and 0.87 (time‐corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury‐induced changes and dedifferentiation.

Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies

“…The main feature of Late-injury biopsies was high expression of the immunoglobulin-associated transcript set, compatible with a plasma cell infiltrate as described in late kidney transplants with atrophy-fibrosis, 22 in late lung transplants, 23 and in late failing heart allografts. 38,39 Although the INTERHEART study only includes SOC biopsies and is not allowed to deliberately perform biopsies for time series analyses, there were some patients with multiple biopsies.…”

“…the immunoglobulin transcripts, which increase with time in kidney and lung transplants and correlate with atrophy-fibrosis in kidney transplants. 22,23…”

“…2 highly expressed in normal hearts 19 ; 4. the immunoglobulin transcripts, which increase with time in kidney and lung transplants and correlate with atrophyfibrosis in kidney transplants. 22,23 Dimensionality reduction, clustering, and data visualization. Principal component analysis (PCA) and AA were described previously.…”

The MMDx®diagnostic system: A critical re‐appraisal of its knowledge gaps and a call for rigorous validation studies

“…Gene expression profiling of TBx is now being explored for the diagnosis of chronic lung allograft dysfunction (CLAD). 43 Another recent study explored the prospects of diagnosing CLAD by taking mucosal biopsies from the third bifurcation of the bronchi (3BMBs). 44 These biopsies are larger than TBx, less subject to sampling error, and associated with fewer complications such as bleeding and pneumothorax, particularly in patients who are unsuitable for TBx, for example due to advanced respiratory compromise.…”

Molecular diagnostics for CLAD: When and where?

“…A key question in developing CLAD diagnostics is whether to focus on immune activation, airway remodeling, or both. The study by Parkes et al 1 investigates transbronchial biopsy (TBB) gene expression changes in CLAD involving 498 TBBs collected across 10 centers. Because the risk for CLAD increases with time, the authors determined differentially expressed genes independently associated with time and CLAD.…”