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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 8

F4/80+ macrophage infiltration and cutaneous fibrosis post BMT is CCL2/CCR2 independent.

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F4/80+ macrophage infiltration and cutaneous fibrosis post BMT is CCL2/C...
(A) Serum CCL2 (MCP-1; pg/ml) in lethally irradiated B6D2F1 mice that received B6 BM plus T cell (Allo) or TCD grafts 7, 14, 21, and 28 days after transplantation (days 7 and 14, *P = 0.015; day 21, *P = 0.035; day 28, **P = 0.009). n = 4–6/group. (B) Lethally irradiated B6D2F1 mice received BM plus T cell grafts from B6 or Ccr2–/– donors. IHC to detect F4/80 expression at day 28 shows that recipients of Ccr2–/– grafts had F4/80+ macrophage infiltration levels similar to those in mice that received WT grafts, quantified in C as positive/pixels/mm2 (P = 0.207) (n = 9 WT, n = 8 KO, n = 5 TCD). (D and E) H&E-stained images and semiquantitative histopathology (n = 15 WT, n = 14 KO, n = 6 TCD) illustrating that recipients of Ccr2–/– grafts had cutaneous pathology similar to that of recipients of WT grafts (P = 0.720). (F and G) Lethally irradiated B6 mice received G-CSF–mobilized BALB/c or TCD grafts and were treated with hamster IgG or anti-CCL2 from days 7 to 33 (n = 15 hamster IgG, n = 14 anti-CCL2, n = 3 TCD). Similar levels of F4/80+ infiltration were noted in both groups, quantified in G as positive/pixels/mm2 (P = 0.2727). (H) Semiquantitative histopathology score illustrating that anti-CCL2 administration had no effect on cutaneous pathology (P = 0.922). (I) Representative dot plots of recipient PB monocyte and macrophage analysis at day 21. Numbers in each dot plot indicate the percentage of Ly6Chi cells (top 2 quadrants) and Ly6Clo cells (bottom 2 quadrants) and their expression of CCR2. Results show no significant changes in Ly6Chi or Ly6Clo cell frequencies (n = 4/group). Statistically significant differences were calculated using 2-tailed Mann-Whitney U tests. Data represent the mean ± SEM. Original magnification, ×5.
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