title: CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease.
abstract: Chronic GVHD (cGVHD) is the major cause of late, nonrelapse death following stem cell transplantation and characteristically develops in organs such as skin and lung. Here, we used multiple murine models of cGVHD to investigate the contribution of macrophage populations in the development of cGVHD. Using an established IL-17-dependent sclerodermatous cGVHD model, we confirmed that macrophages infiltrating the skin are derived from donor bone marrow (F4/80+CSF-1R+CD206+iNOS-). Cutaneous cGVHD developed in a CSF-1/CSF-1R-dependent manner, as treatment of recipients after transplantation with CSF-1 exacerbated macrophage infiltration and cutaneous pathology. Additionally, recipients of grafts from Csf1r-/- mice had substantially less macrophage infiltration and cutaneous pathology as compared with those receiving wild-type grafts. Neither CCL2/CCR2 nor GM-CSF/GM-CSFR signaling pathways were required for macrophage infiltration or development of cGVHD. In a different cGVHD model, in which bronchiolitis obliterans is a prominent manifestation, F4/80+ macrophage infiltration was similarly noted in the lungs of recipients after transplantation, and lung cGVHD was also IL-17 and CSF-1/CSF-1R dependent. Importantly, depletion of macrophages using an anti-CSF-1R mAb markedly reduced cutaneous and pulmonary cGVHD. Taken together, these data indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1 signaling after transplantation may prevent and treat cGVHD.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Bianca E
authors.initials: BE
authors.lastname: Teal
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.forename: Mary
authors.initials: M
authors.lastname: Lor
authors.forename: Neil C
authors.initials: NC
authors.lastname: Raffelt
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.forename: Lucie
authors.initials: L
authors.lastname: Leveque
authors.forename: Laetitia
authors.initials: L
authors.lastname: Le Texier
authors.forename: Michelle
authors.initials: M
authors.lastname: Melino
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.forename: Christian
authors.initials: C
authors.lastname: Engwerda
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.forename: Baptiste
authors.initials: B
authors.lastname: Janela
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000473:pathology*; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D033581:Stem Cell Transplantation
chemical_list: D000911:Antibodies, Monoclonal; D020381:Interleukin-17; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor