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


Tugues, Sonia; Amorim, Ana; Spath, Sabine; Martin-Blondel, Guillaume; Schreiner, Bettina; De Feo, Donatella; Lutz, Mirjam; Guscetti, Franco; Apostolova, Petya; Haftmann, Claudia; Hasselblatt, Peter; Núñez, Nicolas G; Hottiger, Michael O; van den Broek, Maries; Manz, Markus G; Zeiser, Robert; Becher, Burkhard (2018). Graft-versus-host disease, but not graft-versus-leukemia immunity, is mediated by GM-CSF–licensed myeloid cells. Science Translational Medicine, 10(469):eaat8410.

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) not only is an effective treatment for several hematologic malignancies but can also result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking nonmalignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically uncouple GvL from GvHD. Using preclinical models of full and partial MHC-mismatched HCT, we here show that the granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by allogeneic T cells distinguishes between the two processes. GM-CSF drives GvHD pathology by licensing donor-derived phagocytes to produce inflammatory mediators such as interleukin-1β and reactive oxygen species. In contrast, GM-CSF did not affect allogeneic T cells or their capacity to eliminate leukemic cells, retaining undiminished GvL responses. Last, tissue biopsies and peripheral blood mononuclear cells from patients with grade IV GvHD showed an elevation of GM-CSF–producing T cells, suggesting that GM-CSF neutralization has translational potential in allo-HCT.

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) not only is an effective treatment for several hematologic malignancies but can also result in potentially life-threatening graft-versus-host disease (GvHD). GvHD is caused by T cells within the allograft attacking nonmalignant host tissues; however, these same T cells mediate the therapeutic graft-versus-leukemia (GvL) response. Thus, there is an urgent need to understand how to mechanistically uncouple GvL from GvHD. Using preclinical models of full and partial MHC-mismatched HCT, we here show that the granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by allogeneic T cells distinguishes between the two processes. GM-CSF drives GvHD pathology by licensing donor-derived phagocytes to produce inflammatory mediators such as interleukin-1β and reactive oxygen species. In contrast, GM-CSF did not affect allogeneic T cells or their capacity to eliminate leukemic cells, retaining undiminished GvL responses. Last, tissue biopsies and peripheral blood mononuclear cells from patients with grade IV GvHD showed an elevation of GM-CSF–producing T cells, suggesting that GM-CSF neutralization has translational potential in allo-HCT.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
05 Vetsuisse Faculty > Institute of Veterinary Pathology
05 Vetsuisse Faculty > Department of Molecular Mechanisms of Disease
07 Faculty of Science > Department of Molecular Mechanisms of Disease

04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:General Medicine
Language:English
Date:28 November 2018
Deposited On:06 Dec 2018 14:59
Last Modified:05 Feb 2019 11:55
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
OA Status:Closed
Publisher DOI:https://doi.org/10.1126/scitranslmed.aat8410
PubMed ID:30487251
Project Information:
  • : FunderSNSF
  • : Grant ID310030_175565
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  • : Grant IDCRSII3_136203
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  • : FunderSNSF
  • : Grant ID316030_150768
  • : Project TitleThe use of Mass-cytometry in multi-parameter immune cell analysis
  • : FunderSNSF
  • : Grant ID310030_146130
  • : Project TitleThe role of the NF?B-inducing kinase NIK in the development and function of cellular immunity
  • : FunderSNSF
  • : Grant ID31003A_152851
  • : Project TitleThe impact of radio- and immunotherapy on local tumor-specific immunity
  • : FunderFP7
  • : Grant ID602239
  • : Project TitleATECT - Advanced T-cell Engineered for Cancer Therapy

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