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

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 10

Lung GVHD develops in an IL-17– and CSF-1R–dependent manner.

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Lung GVHD develops in an IL-17– and CSF-1R–dependent manner. (A) B10.BR ...
(A) B10.BR recipients treated with 120 mg/kg/day cyclophosphamide (days –3 and –2) and lethally irradiated (day –1; 850 cGy) were transplanted with B6 BM with either B6 or Rorc–/– Sp (n = 4/all groups). On day 60 after transplantation, pulmonary function measures were performed. R, resistance; E, elastance; C, compliance. Recipients of Rorc–/– grafts exhibited significantly improved pulmonary function compared with that of WT graft recipients (R: *P = 0.02, *P = 0.03; E: *P = 0.01, *P = 0.03; C: **P = 0.005,*P = 0.01). (B) Similarly, recipients of Csf1r–/– BM plus Csf1r–/– Sp grafts had significantly improved pulmonary function compared with that of mice receiving WT BM plus Csf1r–/– Sp. (R: *P = 0.024,*P = 0.042,*P = 0.0431; E: *P = 0.013,*P = 0.031,*P = 0.01; C: **P = 0.001, **P = 0.0031, *P = 0.033). n = 4. (C) Trichrome staining illustrates reduced collagen deposition in mice that received Csf1r–/– grafts compared with those that received WT grafts, quantified in D as trichrome area/total area (**P = 0.0037; ***P = 0.0005; **P = 0.0023). (E) IHC for F4/80 expression in recipients of WT B6 plus Sp or BM-only grafts that were given control IgG or M279 mAb after transplantation from days 0 to 28 after transplantation. Minimal F4/80+ cells were noted in recipients treated with M279 mAb compared with those detected in control IgG–treated recipients. (F) Lung function parameters confirmed an improvement in lung function after M279 mAb treatment (R: **P = 0.001,**P = 0.008; E: **P = 0.003, *P = 0.034; C: **P = 0.004,*P = 0.02). n = 4. (G) Trichrome staining confirmed that M279 mAb treatment significantly reduced collagen deposition, quantified in H (**P = 0.017; ***P = 0.0003). Statistically significant differences were calculated using unpaired t tests. Data represent the mean ± SEM. Original magnification, ×20.