Chronic graft-versus-host disease (cGVHD) significantly contributes to late mortality after allogeneic stem cell transplantation, with bronchiolitis obliterans syndrome (BOS) being a particularly lethal and treatment-resistant complication despite available therapies. Bromodomain and Extra terminal (BET) proteins are epigenetic readers driving inflammatory transcriptional programs across multiple cell types. We hypothesized that BET inhibition would suppress inflammatory T and B cells while also decreasing macrophage polarization to a profibrotic phenotype, alleviating disease. In an established BOS cGVHD model, BET inhibition reduced germinal center formation and response through a reduction of the CXCL13:CXCR5 axis, inflammatory Tfh/GC B cells in the spleen along with a reduction in plasma cell infiltration within the lung. Mice with cGVHD had elevated pathogenic IgG1 and IgM, both in circulation and deposited on lung tissue, which was attenuated under BET inhibition. Single-cell RNA sequencing analysis revealed distinct cell states in the BOS lung vs. control. In cGVHD mice, GSEA analysis revealed upregulation of profibrotic Arginase1 and Tgfb1 expression in alveolar macrophages (AM) and interstitial macrophages (IM), which was significantly reduced with BET inhibition. Furthermore, BET inhibition targeted lung-infiltrating M2 macrophages, through selective depletion of CD206+FcgR+ IMs and AMs, ultimately resulting in reduced collagen deposition and improved lung function. Our findings reveal a previously unrecognized mechanistic axis of BET regulation during cGVHD fibrosis and highlight BET inhibition as a promising therapeutic strategy.
Kumar et al. (Mon,) studied this question.