Targeting mannose receptor (CD206)+, pro-fibrotic macrophages to halt lung fibrosis progression in chronic graft-versus-host disease 2251444

Introduction TGFβ−secreting, CD206+ profibrotic macrophages (macs) are key chronic graft-versus-host disease (cGVHD) drivers. Global depletion of macs could compromise protective immunity; therefore, we targeted CD206 + (mannose receptor) macs with mannosylated albumin nanoparticles (MANPs) containing TGFβ siRNA or non-targeting (NT) siRNA for control. A published bleomycin pulmonary fibrosis model showed disease prevention post TGFβ-MANPs internalization by CD206+ monocyte-derived alveolar macs. CD206+ TGFβ+ macs are also critical in sclerodermatous (Scl) GVHD (B10D2>Balb/c). We show that mice with established multiorgan cGVHD/bronchiolitis obliterans (BO) exhibit a progressive increase in lung tissue profibrotic macs (d49 vs. d28) highlighting their pathogenic role. Methods In our cGVHD/BO model, B10.BR recipients receive B6 bone marrow (BM) and a low dose of T cells (control = BM only). Co-culture of CD206 + (M2-like) and CD206neg (M1-like) macs confirmed that MANPs were preferentially internalized by CD206+ macs and effectively reduced TGFβ protein and mRNA with no effect on CD206neg macs. In vivo, MANPs are delivered intravenously 2x/week starting at d28 post transplantation. Results Compared to BM only controls, d49 cGVHD/BO mice had a significant increase (1.5-fold) in lung CD206+ macs frequency (p = 0.0010) and these cells had a 2.5-fold increase in TGFβ expression (p = 0.0070) by flow cytometry fluorescent intensity. TGFβ siRNA vs NT siRNA—loaded MANPs delivered i.v. to cGVHD/BO mice improved lung function to levels comparable to BM controls (n = 10/group): resistance (p < 0.0001), elastance (p < 0.05), compliance (p < 0.05). Early studies using MANP-based delivery of TGFβ siRNA in Scl GVHD improved skin scores (p < 0.0001) compared to NT siRNA delivery. Further studies with MANPs in Scl GVHD are ongoing. Conclusion These results identify CD206+ macs as a tractable therapeutic target with high selectivity and highlight MANP-based siRNA delivery as a promising strategy to limit cGVHD-driven pulmonary fibrosis.