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CSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host disease
Kylie A. Alexander, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Kylie A. Alexander, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4266-4280. https://doi.org/10.1172/JCI75935.
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Research Article Immunology

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

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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

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. Blazar, Geoffrey R. Hill, Kelli P.A. MacDonald

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Figure 2

F4/80+ macrophages infiltrating the skin after transplantation are donor M2–like macrophages that express CSF-1R.

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F4/80+ macrophages infiltrating the skin after transplantation are donor...
(A) Representative IHC images from lethally irradiated B6 mice that received G-CSF–mobilized BALB/c (CD45.1) or G-CSF–mobilized TCD grafts. IHC to analyze F4/80, CD45.1, CD206, and iNOS expression illustrates that at day 21 after transplantation, donor M2–like macrophages were present within the skin (F4/80+, CD45.1+, CD206+, and iNOS–). Minimal donor M2–like macrophage infiltrate was detected in mice that received TCD grafts. Original magnification, ×5. (B) Representative IF images 28 days after transplantation from skin of lethally irradiated B6D2F1 mice that received BM plus T cell grafts from MacGreen transgenic mice (Csf1r promoter driving EGFP). n = 3/time point. Original magnification, ×20. IF confirmed that CSF-1R+ cells (green) were also F4/80+ (red); white arrows.
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