BET inhibition blunts antibody production and macrophage-mediated fibrosis to restore lung function in murine cGVHD - PubMed

6 hours ago

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality post allogeneic stem cell transplantation, with bronchiolitis obliterans syndrome (BOS) being a lethal complication.
BET proteins are epigenetic readers that drive inflammatory transcriptional programs in various cell types.
BET inhibition was hypothesized to suppress inflammatory T and B cells and reduce macrophage polarization to a profibrotic phenotype, thereby alleviating cGVHD.
In a BOS cGVHD model, BET inhibition reduced germinal center formation and response by affecting the CXCL13:CXCR5 axis, leading to fewer inflammatory Tfh/GC B cells in the spleen and reduced plasma cell infiltration in the lung.
BET inhibition attenuated elevated pathogenic IgG1 and IgM levels in circulation and lung tissue deposition in cGVHD mice.
Single-cell RNA sequencing showed distinct cell states in BOS lungs vs. controls, with upregulation of profibrotic genes (Arginase1, Tgfb1) in alveolar and interstitial macrophages (AM/IM), which was reduced by BET inhibition.
BET inhibition selectively depleted CD206+FcgR+ IMs and AMs, reducing collagen deposition and improving lung function.
The study highlights BET inhibition as a promising therapeutic strategy for cGVHD fibrosis.

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