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).
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
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