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Cited by 435Adenosine and Purinergic SignalingHematopoietic Stem Cell TransplantationEffects of Radiation Exposure

Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R

Wilhelm, Konrad, Ganesan, Jayanthi, Müller, Tobias, Dürr, Christoph, Grimm, Melanie, Beilhack, Andreas, Krempl, Christine D, Sorichter, Stephan +12 more·2010·Nature Medicine
DOI 10.1038/nm.2242
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Abstract

Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions, and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-γ (IFN-γ) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.

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Crossref · 10.1038/nm.2242

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  • In a disease state such as infection or brain disease, extracellular ATP levels largely increase and activate P2X7 receptors.

    “Conversely, in a disease state as infection or brain disease, extracellular ATP levels largely increase and activate P2X7 receptors [68–70].”

    From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [69]

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Authors
Wilhelm, K., Ganesan, J., Müller, T., Dürr, C., Grimm, M., Beilhack, A., Krempl, C. D., Sorichter, S., Gerlach, U. V., Jüttner, E., Zerweck, A., Gärtner, F., Pellegatti, P., Di Virgilio, F., Ferrari, D., Kambham, N., Fisch, P., Finke, J., Idzko, M., & Zeiser, R.
Affiliations
  • University of Freiburg (DE)
  • Universitätsklinikum Würzburg (DE)
  • University of Würzburg (DE)
  • University of Ferrara (IT)
  • Stanford Medicine (US)
Corresponding author
  • Idzko, Marco
  • Zeiser, Robert
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-11-21
Volume
16
Issue
12
Pages
1434-1438
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2242
OpenAlex
W2129388928
Cited by
435
References
30
Citations by year
2026: 10 · 2025: 25 · 2024: 22 · 2023: 28 · 2022: 28 · 2021: 40 · 2020: 29 · 2019: 29 · 2018: 25 · 2017: 31 · 2016: 29 · 2015: 26 · 2014: 39 · 2013: 27 · 2012: 40
FWCI
16.17
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords
graft-versus-host disease, P2X7 receptor, extracellular ATP, damage-associated molecular patterns, antigen-presenting cells, STAT1 phosphorylation, interferon-gamma, regulatory T cells, peritoneal fluid, transplantation tolerance, allograft rejection, systemic inflammatory response syndrome
MeSH terms
Adenosine Triphosphate, Animals, Antigen-Presenting Cells, Ascites, Ascitic Fluid, Extracellular Space, Flow Cytometry, Graft vs Host Disease, Humans, Interferon-gamma, Mice, Inbred C57BL, Models, Biological, Phosphorylation, Whole-Body Irradiation, Bone Marrow Transplantation, Cytokines, B7-1 Antigen, Mice, Knockout, Gastrointestinal Tract, T-Lymphocytes, Regulatory, STAT1 Transcription Factor, Mice, B7-2 Antigen, Receptors, Purinergic P2X7

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