title: Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R.
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.
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Wilhelm
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Ganesan
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.forename: Christoph
authors.initials: C
authors.lastname: Dürr
authors.forename: Melanie
authors.initials: M
authors.lastname: Grimm
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: Christine D
authors.initials: CD
authors.lastname: Krempl
authors.forename: Stephan
authors.initials: S
authors.lastname: Sorichter
authors.forename: Ulrike V
authors.initials: UV
authors.lastname: Gerlach
authors.forename: Eva
authors.initials: E
authors.lastname: Jüttner
authors.forename: Alf
authors.initials: A
authors.lastname: Zerweck
authors.forename: Frank
authors.initials: F
authors.lastname: Gärtner
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pellegatti
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrari
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D001201:Ascites / Q000378:metabolism; D001202:Ascitic Fluid / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000276:immunology; D005110:Extracellular Space / Q000378:metabolism*; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000378:metabolism; D006086:Graft vs Host Disease / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D058486:Receptors, Purinergic P2X7; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D000255:Adenosine Triphosphate