Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R
| Autor: | Eva Jüttner, Ulrike V. Gerlach, Andreas Beilhack, Alf Zerweck, Konrad Wilhelm, Neeraja Kambham, Tobias Müller, Francesco Di Virgilio, Jürgen Finke, Paul Fisch, Robert Zeiser, Christine D. Krempl, Marco Idzko, Christoph Dürr, Davide Ferrari, Patrizia Pellegatti, Melanie Grimm, Stephan Sorichter, Jayanthi Ganesan, Frank Gärtner |
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| Rok vydání: | 2010 |
| Předmět: |
Regulatory T cell
T cell Antigen-Presenting Cells Graft vs Host Disease Biology Models Biological T-Lymphocytes Regulatory General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine Interferon-gamma Mice Adenosine Triphosphate Immune system Interferon medicine Animals Ascitic Fluid Humans Phosphorylation Bone Marrow Transplantation Mice Knockout CD86 Ascites General Medicine Flow Cytometry medicine.disease Cell biology Gastrointestinal Tract Mice Inbred C57BL STAT1 Transcription Factor medicine.anatomical_structure Graft-versus-host disease Immunology B7-1 Antigen Cytokines B7-2 Antigen Receptors Purinergic P2X7 Extracellular Space Whole-Body Irradiation CD80 medicine.drug |
| Zdroj: | Nature Medicine. 16:1434-1438 |
| ISSN: | 1546-170X 1078-8956 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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