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Donor monocyte–derived macrophages promote human acute graft-versus-host disease
Laura Jardine, … , A.J. Simpson, Matthew Collin
Laura Jardine, … , A.J. Simpson, Matthew Collin
Published May 26, 2020
Citation Information: J Clin Invest. 2020;130(9):4574-4586. https://doi.org/10.1172/JCI133909.
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Research Article Immunology Article has an altmetric score of 6

Donor monocyte–derived macrophages promote human acute graft-versus-host disease

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Abstract

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 SIRPα and S100A8/9 transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and costimulation. 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 keratinocyte 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.

Authors

Laura Jardine, Urszula Cytlak, Merry Gunawan, Gary Reynolds, Kile Green, Xiao-Nong Wang, Sarah Pagan, Maharani Paramitha, Christopher A. Lamb, Anna K. Long, Erin Hurst, Smeera Nair, Graham H. Jackson, Amy Publicover, Venetia Bigley, Muzlifah Haniffa, A.J. Simpson, Matthew Collin

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Figure 6

Allostimulated monocytes resemble GVHD macrophages.

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Allostimulated monocytes resemble GVHD macrophages.
(A) Radial plots of ...
(A) Radial plots of cytokine quantity in supernatants from GVHD explants cultured for 48 hours (red line) and BMT donor-recipient MLRs cultured for 7 days (purple line). Lines show mean cytokine concentration from n = 12 (GVHD) and n = 6 (MLR) experiments. IL-9, IL12p70, IL-23, IL-31, and TNF-β are not shown because they were not detected in any specimens. (B) May-Grünwald Giemsa cytospin morphology, scatter properties, and CD11c/CD14 expression by MLR macrophages, isolated on day 7. Scale bar: 20 μM. (C) Expression of selected antigens, previously used to define GVHD macrophages, by allostimulated CD11c+CD14+ cells from BMT donor-recipient MLRs (specific staining in purple; isotype control in gray). Representative histograms from more than 3 analyses are shown. (D) Expression of cytotoxic effector genes in CD14+ blood monocytes, skin CD11c+CD14+ cells, and MLR macrophages. Columns indicate mean and bars SEM of n = 3–6 values; *P < 0.05, Kruskal-Wallis test with P values from Dunn’s multiple comparison tests is shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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