CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease

Kylie A. Alexander, Ryan Flynn, Katie E. Lineburg, Rachel D. Kuns, Bianca E. Teal, Stuart D. Olver, Mary Lor, Neil C. Raffelt, Motoko Koyama, Lucie Leveque, Laetitia Le Texier, Michelle Melino, Kate A. Markey, Antiopi Varelias, Christian Engwerda, Jonathan S. Serody, Baptiste Janela, Florent Ginhoux, Andrew D. Clouston, Bruce R. BlazarGeoffrey R. Hill, Kelli P A MacDonald

Research output: Contribution to journalArticle

79 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4266-4280
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number10
DOIs
StatePublished - Oct 1 2014

Fingerprint Dive into the research topics of 'CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease'. Together they form a unique fingerprint.

  • Cite this

    Alexander, K. A., Flynn, R., Lineburg, K. E., Kuns, R. D., Teal, B. E., Olver, S. D., Lor, M., Raffelt, N. C., Koyama, M., Leveque, L., Le Texier, L., Melino, M., Markey, K. A., Varelias, A., Engwerda, C., Serody, J. S., Janela, B., Ginhoux, F., Clouston, A. D., ... MacDonald, K. P. A. (2014). CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. Journal of Clinical Investigation, 124(10), 4266-4280. https://doi.org/10.1172/JCI75935