Macrophage verses host

Stem cell transplantation can be life saving for patients with aggressive forms of cancer that are unresponsive to other available treatments. Unfortunately, patients that receive stem cells from an autologous donor are at risk of developing graft verse host disease (GVHD), in which the immune cells generated from the donor stem cells mount a response against the host tissue. Chronic GVHD (cGVHD) develops over time and shares many features of autoimmune disorders such as fibrosis, which hinders organ function; however, the drivers of cGVHD are poorly understood. Using two murine models of cGVHD, Kylie Alexander and colleagues at the QIMR Berghofer Medical Research Institute investigated the contribution of macrophages to the development of cGVHD.  In a cutaneous cGVHD model, donor-derived macrophages infiltrated host skin tissue, and treatment of animals with CSF-1 after transplantation exacerbated damage. Mice that received stem cells from Csf1r-/- mice had reduced numbers of macrophages infiltrating the skin and less cutaneous pathology. Importantly, treatment of mice with and anti-CSF-1R antibody reduced cGVHD in both the cutaneous and pulmonary cGVHD mouse models. Together these results indicate that donor macrophages mediate the development of cGVHD and suggest that targeting CSF-1/CSF-1R signaling may benefit patients receiving allogeneic stem cell transplants. The accompanying image shows the differences in cutaneous fibrosis development in recipients of WT stem cells (left) and Csf1r-/- stem cells (right). 

Published August 26, 2014, by Corinne Williams

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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

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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