학술논문
Type‐1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction
Document Type
article
Author
Iasella, Carlo J; Hoji, Aki; Popescu, Iulia; Wei, Jianxin; Snyder, Mark E; Zhang, Yingze; Xu, Wei; Iouchmanov, Vera; Koshy, Ritchie; Brown, Mark; Fung, Monica; Langelier, Charles; Lendermon, Elizabeth A; Dugger, Daniel; Shah, Rupal; Lee, Joyce; Johnson, Bruce; Golden, Jeffrey; Leard, Lorriana E; Kleinhenz, Mary Ellen; Kilaru, Silpa; Hays, Steven R; Singer, Jonathan P; Sanchez, Pablo G; Morrell, Matthew R; Pilewski, Joseph M; Greenland, John R; Chen, Kong; McDyer, John F
Source
American Journal of Transplantation. 21(6)
Subject
Language
Abstract
Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1β as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.