TY - JOUR T1 - Donor monocyte-derived macrophages promote human acute graft versus host disease JF - bioRxiv DO - 10.1101/787036 SP - 787036 AU - Laura Jardine AU - Urszula Cytlak AU - Merry Gunawan AU - Gary Reynolds AU - Kile Green AU - Xiao-Nong Wang AU - Sarah Pagan AU - Maharani Pradnya AU - Christopher A Lamb AU - Anna K Long AU - Erin Hurst AU - Smeera Nair AU - Graham Jackson AU - Amy Publicover AU - Venetia Bigley AU - Muzlifah Haniffa AU - A. John Simpson AU - Matthew Collin Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/30/787036.abstract N2 - Myelopoiesis is invariably present, and contributes to pathology, in animal models of graft versus host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties and role in pathogenesis of these cells, we isolated single cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and nanostring gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRPĪ± and S100A8/9, and transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and co-stimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells, and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a cell line and mediated pathological damage to skin explants, independently of T cells. Together, these results define the origin, functional properties and potential pathogenic roles of human GVHD macrophages. ER -