What question did this study set out to answer?

This research aims to understand the cellular mechanisms of acute cellular rejection in lung transplants and explore potential therapies for chronic lung allograft dysfunction.

February 26, 2026Open Access

Human Lung Allografts Experience Persistent Fibrogenic Shift Following Acute Cellular Rejection

Key Points

This research aims to understand the cellular mechanisms of acute cellular rejection in lung transplants and explore potential therapies for chronic lung allograft dysfunction.
Conducted single cell RNA-sequencing on lung tissue from 8 patients with acute cellular rejection and surveillance biopsies.
Validated findings using gene microarray analysis and immunofluorescence.
Performed single cell ATAC-seq for additional insights.
Identified persistent activation of TGF-β and mTOR pathways in samples with acute cellular rejection.
Observed myofibroblast gene signatures indicating fibrosis without traditional epithelial transitions.
Found increased cytotoxic T cells and dendritic cells, while natural killer cells were reduced in acute cellular rejection samples.

Abstract

AbstractRationale Acute cellular rejection (ACR) remains a significant challenge in lung transplantation, with incomplete understanding of its molecular mechanisms and pathways linking ACR to chronic lung allograft dysfunction (CLAD). Objectives To characterize the cellular and molecular mechanisms underlying ACR in lung allografts using single cell genomics and identify potential therapeutic targets for CLAD. Methods Single cell RNA-sequencing of freshly collected lung tissue was performed across 8 pediatric and adult patients with ACR, Resolved ACR, and surveillance biopsies without ACR. Validation included gene microarray analysis, immunofluorescence, and single cell ATAC-seq. Measurements and Main Results Gene set enrichment analysis revealed persistent TGF-β signaling and PI3K/AKT/mTOR pathway activation in both ACR and Resolved samples, validated by immunofluorescence showing sustained elevation of mTOR activation marker phosphorylated-S6 ribosomal protein and COL3A1. Fibrogenic cells exhibited myofibroblast gene signatures via mesenchymal state transitions rather than epithelial- or endothelial-to-mesenchymal transition. Cell communication analysis showed increased Type II Interferon signaling, with Jak/Stat pathway activation in endothelial and basal cells, and reduced VE-Cadherin staining in ACR. Compositional analysis revealed increased cytotoxic, memory T cells and dendritic cells, with persistent reduction of natural killer cells in ACR and Resolved. Donor/recipient analysis revealed predominantly recipient-derived immune cells in ACR. Conclusions Persistent TGF-β and mTOR pathway activation following histologic ACR resolution provides molecular insight into ACR-CLAD linkage and suggests mTOR inhibition and TGF-β blockade as potential therapeutic mechanisms to prevent CLAD. Data Availability To review GEO accession GSE274199 (scRNA-seq): Go to https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE274199 Enter token qbojyyaitncvbod into the box Code will be made available upon publication

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Potter et al. (Sun,) studied this question.

synapsesocial.com/papers/699fe28895ddcd3a253e63a7 https://doi.org/https://doi.org/10.1016/j.healun.2026.02.1666

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