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Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.


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.

SUBMITTER: Iasella CJ 

PROVIDER: S-EPMC8607839 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Iasella Carlo J CJ   Hoji Aki A   Popescu Iulia I   Wei Jianxin J   Snyder Mark E ME   Zhang Yingze Y   Xu Wei W   Iouchmanov Vera V   Koshy Ritchie R   Brown Mark M   Fung Monica M   Langelier Charles C   Lendermon Elizabeth A EA   Dugger Daniel D   Shah Rupal R   Lee Joyce J   Johnson Bruce B   Golden Jeffrey J   Leard Lorriana E LE   Ellen Kleinhenz Mary M   Kilaru Silpa S   Hays Steven R SR   Singer Jonathan P JP   Sanchez Pablo G PG   Morrell Matthew R MR   Pilewski Joseph M JM   Greenland John R JR   Chen Kong K   McDyer John F JF  

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20201120 6


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)  ...[more]

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