Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF–licensed myeloid cells

Tugues, Sònia; Amorim, Ana; Spath, Sabine; Martin‐Blondel, Guillaume; Schreiner, Bettina; Feo, Donatella De; Lutz, Mirjam; Guscetti, Franco; Apostolova, Petya; Haftmann, Claudia; Hasselblatt, Peter; Núñez, Nicolás Gonzalo; Hottiger, Michael O.; Broek, Maries van den; Manz, Markus G.; Zeiser, Robert; Becher, Burkhard

doi:10.1126/scitranslmed.aat8410

Cited by 66 publications

(76 citation statements)

References 46 publications

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“…Where they have been isolated from primary human tissues, their function has been described as regulatory, in comparison with DC (33,34). Our findings that GVHD macrophages have functional attributes capable of promoting GVHD provide an important corroboration of recent mouse models describing the dependence of GVHD pathology upon donor myeloid cells activated by T cell-derived GM-CSF (19).…”

Section: Myeloid Cells Found In Gvhd Have Previously Been Characterizsupporting

confidence: 79%

“…Unlike T cells in the human adult, which may take more than 2 years to recover after transplantation, myeloid cells are continuously generated, and rapid immune reconstitution is possible following myeloid-targeted interventions. The ability to isolate discrete mechanisms that govern the infiltration of tissues by myeloid cells, such as GM-CSF dependence, may also offer a means of minimising GVHD without compromising GVL (19).…”

Section: Gvhd Macrophages Demonstrated Enhanced T Cell Stimulatory Fumentioning

confidence: 99%

“…Knock-out of the ATP receptor P2Y2 on recipient monocytes reduces GVHD lethality (18). Most recently, a specific role of T cell-derived GM-CSF was described in promoting the differentiation of effector macrophages (19).…”

Section: Introductionmentioning

confidence: 99%

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

Jardine

Cytlak

Gunawan

et al. 2019

Preprint

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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, 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.

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Section: Myeloid Cells Found In Gvhd Have Previously Been Characterizsupporting

confidence: 79%

Section: Gvhd Macrophages Demonstrated Enhanced T Cell Stimulatory Fumentioning

confidence: 99%

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

Jardine

Cytlak

Gunawan

et al. 2019

Preprint

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“…In graft-versus-host disease, high GM-CSF produced by allogeneic T cells induces donorderived myeloid cells to produce inflammatory cytokines, which drives pathology 74 . In hepatocellular carcinoma, tumor cells produce high amounts of GM-CSF that recruit myeloid derived suppressor cells to induce immune tolerance and increase PD-L1 expression 75 .…”

Section: Gm-csf Production By T Cells Activates Myeloid Cells For Infmentioning

confidence: 99%

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

Ahl

Hopkins

Xiang

et al. 2020

Preprint

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A complex interaction of anabolic and catabolic metabolism underpins the ability of leukocytes to mount an immune response. Their capacity to respond and adapt to changing environments by metabolic reprogramming is crucial to their effector function. However, current methods lack the ability to interrogate this network of metabolic pathways at the single cell level within a heterogeneous population. Here we present Met-Flow, a novel flow cytometry-based method that captures the metabolic state of immune cells by targeting key proteins and rate-limiting enzymes across multiple pathways. We demonstrate the ability to simultaneously measure divergent metabolic profiles and dynamic remodeling in human peripheral blood mononuclear cells. Using Met-Flow, we discovered that glucose restriction and metabolic remodeling drive the expansion of an inflammatory central memory T cell subset. This method captures the complex metabolic state of any cell as it relates to its phenotype and function, leading to a greater understanding of the role of metabolic heterogeneity in immune responses.

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“…By using a light inducible photo‐converter system it was shown that neutrophils that were photo‐converted in the terminal ileum were later detected in the mesenteric lymph nodes. Granulocyte‐macrophage colony‐stimulating factor drives GVHD pathology by licensing donor‐derived myeloid phagocytic cells to produce inflammatory mediators, such as interleukin (IL) 1β and ROS and promote GVHD (Tugues et al , ).…”

Section: Early Tissue Damage and Innate Immune Cells In Gvhdmentioning

confidence: 99%

Advances in understanding the pathogenesis of graft‐versus‐host disease

Zeiser

2019

Br J Haematol

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Summary Acute graft‐versus‐host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). The emergence of different immuno‐prophylaxis strategies, such as post‐transplant cyclophosphamide or anti‐thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno‐stimulatory agents, including immune checkpoint inhibitors or anti‐neoplastic immune‐modifiers, like lenalidomide, given before or after allo‐HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno‐regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro‐inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti‐bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies.

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Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF–licensed myeloid cells

Cited by 66 publications

References 46 publications

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

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

A novel strategy for single-cell metabolic analysis highlights dynamic changes in immune subpopulations

Advances in understanding the pathogenesis of graft‐versus‐host disease

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