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Myeloid-avid mTOR-inhibiting nanobiologic attenuates allograft fibrosis after lung transplantation

ABSTRACT: Chronic lung allograft dysfunction (CLAD) is characterized by fibrotic graft remodeling and limits long-term survival after pulmonary transplantation. Despite clinical evidence that myeloid cells drive conditions that increase the risk of CLAD development, contemporary immunosuppression primarily target lymphocytes. We evaluated an mTOR inhibiting nanobiologic (mTORi-NB) targeting myeloid cells and their progenitors in a semi-allogeneic mouse model of CLAD. We found that the mTORi-NB preferentially targeted myeloid and endothelial cells in the allografts. Brief peri-operative therapy with the mTORi-NB reduced early macrophage graft infiltration and inhibited acute inflammation. In mTORi-NB-treated lung recipients, transcriptomic analysis revealed downregulation of fibrotic genes in macrophages and type I (AT1) and type II (AT2) alveolar epithelial cells, known drivers of pulmonary fibrogenesis. We also observed upregulation of anti-fibrotic genes in macrophages after treatment with mTORi-NB, as well as reduction of allograft fibrosis, associated with preservation of AT2 cells. Our findings suggest that myeloid-avid immunosuppression may be a promising approach for inhibiting CLAD.

ORGANISM(S): Mus musculus

PROVIDER: GSE314602 | GEO | 2026/06/29

REPOSITORIES: GEO

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