Airway molecular signatures in antibody-mediated lung transplant rejection

Severe antibody-mediated rejection (AMR) is associated with chronic lung allograft dysfunction (CLAD) and death in lung transplant recipients. However, AMR diagnostics are imprecise, and new biomarkers are needed. We assessed whether airway inflammation gene signatures could distinguish AMR cases from controls. We analyzed small airway brush RNA sequencing from 16 AMR cases and 39 controls across 2 centers. We compared gene signatures for complement activation, molecular target of rapamycin (mTOR) signaling, and natural killer cell-mediated injury. Differential gene expression and pathway analyses sought AMR molecular features. Additionally, we evaluated the airway inflammation 2 (AI2) score, previously associated with CLAD and graft failure, in relation to AMR clinical features and survival outcomes. AMR airway brushes demonstrated transcriptional evidence of airway inflammation and upregulation of complement and natural killer cell pathways. The AI2 score was significantly elevated in AMR cases (P < .001) and was associated with AMR-compatible histology, donor-specific antibodies, complement binding, and acute graft dysfunction. Increasing AI2 scores were associated with worse retransplant-free survival, independent of other AMR features. In small airways, lung transplant AMR predominantly exhibits molecular features of cellular rejection rather than a distinct humoral rejection profile. Airway brush transcriptomics may provide a valuable tool for characterizing and prognosticating suspected AMR.