BET Inhibition Blunts Antibody Production and Macrophage-mediated Fibrosis to Restore Lung Function in Murine cGVHD

Researchers at The Ohio State University have demonstrated that BET inhibition can reverse key immunologic and fibrotic features of bronchiolitis obliterans syndrome, a severe pulmonary form of chronic graft-versus-host disease. Published in Blood, this preclinical study showed that treatment with the BET inhibitor OPN-51107 reduced pathogenic germinal center responses, blunted profibrotic macrophage programs, decreased collagen deposition, and restored lung function in a murine cGVHD model. Overall, BET inhibition acts across multiple disease-driving compartments, including Tfh and B cells, antibody production, macrophage polarization, and fibroblast-mediated fibrosis, making it a potentially useful multi-compartment therapeutic strategy for treatment-refractory BOS.

Bronchiolitis obliterans syndrome remains one of the most lethal and treatment-resistant manifestations of chronic GVHD, and currently available therapies often provide only partial benefit, especially in severe disease. Because cGVHD is driven not only by inflammatory T and B cell interactions but also by macrophage-dependent tissue remodeling and fibrosis, the investigators hypothesized that BET proteins might function as upstream epigenetic regulators of several pathogenic pathways at once. They used an established murine BOS model in which B10.BR recipients received allogeneic transplant followed by splenocytes to induce cGVHD, then began OPN-51107 treatment on day 28, after disease was established, through day 55.

Mechanistically, the authors show that BET inhibition reduced circulating CXCL13 and CXCR5 expression on both CD4 T cells and B cells, decreasing splenic PD1hiCXCR5+ Tfh cells and FAS+GL7+ germinal center B cells, and lowering lung infiltration by IgG1+ B cells and mature plasma cells. Single-cell RNA sequencing identified 22 lung cell populations and showed that fibroblasts, alveolar macrophages, and interstitial macrophages carried the major BOS-associated effector programs. BET inhibition selectively reversed macrophage profibrotic states, reducing Arginase1 and Tgfb1 expression and depleting CD206+FcγR+ M2 interstitial and alveolar macrophages. Histologically, cGVHD lungs showed increased collagen deposition that was attenuated by BET inhibition, and functionally the treated mice had significantly improved airway resistance, elastance, and compliance. These findings demonstrate that BET inhibition does not simply suppress inflammation, but interrupts the antibody/macrophage/fibroblast axis that drives irreversible lung fibrosis, supporting clinical exploration of BET inhibitors for pulmonary chronic GVHD.

Reference:

Kumar R, Neidemire-Colley L, Garfinkle EA, et al. BET inhibition blunts antibody production and macrophage-mediated fibrosis to restore lung function in murine cGVHD. Blood. Published online March 2, 2026. http://doi.org/10.1182/blood.2025031983