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Lookup NU author(s): Dr Laura JardineORCiD, Dr Urszula Cytlak-ChaudhuriORCiD, Dr Merry Gunawan, Dr Gary ReynoldsORCiD, Dr Kile GreenORCiD, Dr Xiao WangORCiD, Sarah Pagan, Professor Chris LambORCiD, Anna Long, Professor Graham Jackson, Dr Amy Publicover, Dr Venetia BigleyORCiD, Professor Muzlifah Haniffa, Professor John SimpsonORCiD, Professor Matthew CollinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Jardine L, Cytlak U, Gunawan M, Reynolds G, Green K, Wang XN, Pagan S, Paramitha M, Lamb CA, Long A, Hurst E, Nair S, Jackson GH, Publicover A, Bigley V, Haniffa M, Simpson AJ, Collin M
Publication type: Article
Publication status: Published
Journal: The Journal of Clinical Investigation
Year: 2020
Volume: 130
Issue: 9
Pages: 4574-4586
Print publication date: 01/09/2020
Online publication date: 26/05/2020
Acceptance date: 19/05/2020
Date deposited: 06/06/2020
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: https://doi.org/10.1172/JCI133909
DOI: 10.1172/JCI133909
PubMed id: 32453711
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