Purpose
Lung transplant patients with AMR often fail treatment. Defining the mechanisms involved may identify better drug targets, as well as biomarkers that can be used to tailor therapies and prevent downstream chronic lung allograft dysfunction (CLAD). Here, we perform whole-genome DNA methylome analysis to define the mechanisms associated to AMR non-responders.
Methods
The case-control design included 26 patients with AMR and 21 controls, matched for race, sex and age.
Measurement
DNA was extracted from BAL cells for whole-genome bisulfite sequencing; controls samples were post-transplant time-matched to AMR samples.
Analysis
AMR patients were adjudicated as Non-responders if they developed CLAD within 2 years of diagnosis, otherwise, AMR patients were grouped as Responders. Bisulfite sequence reads were analyzed with an in-house computational workflow to map BAL cell-type composition, and molecular pathway differences between groups.
Results
AMR (14 Non-responders, 12 Responders) were diagnosed at a median 9.6 months post-transplant. We identified different BAL cell-type compositions; monocyte predominance for Responders vs. neutrophilic predominance for non-responders (p<0.01). The different cell composition was present before AMR diagnosis and persistent after treatment. Cell-composition was similar for Responders and Controls (Fig A). We also identified pathway differences; Responders showed classic complement activation pathways, while Non-responders showed NK-cells and other antibody-mediated cytotoxic pathways (Fig B).
Conclusion
We identified different BAL cell composition and mechanisms that correlate with response to AMR treatment. If validated, these features are poised to identify novel drug targets and may serve as biomarkers to tailor AMR treatment.
Article info
Identification
Copyright
© 2022 Published by Elsevier Inc.
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