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

Lookup NU author(s): Dr Laura Jardine, Dr Urszula Cytlak-Chaudhuri, Dr Merry Gunawan, Dr Gary Reynolds, Dr Kile Green, Dr Xiao Wang, Sarah Pagan, Dr Chris Lamb, Anna Long, Professor Graham Jackson, Dr Amy Publicover, Dr Venetia Bigley, Professor Muzlifah Haniffa, Professor John Simpson, Professor Matthew Collin

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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 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.


Publication metadata

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

Pages: ePub ahead of print

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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