Graft-versus-host Disease Is Enhanced by Extracellular ATP Activating P2X7R

Nat Med. 2010 Dec;16(12):1434-8. doi: 10.1038/nm.2242. Epub 2010 Nov 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Antigen-Presenting Cells / metabolism
  • Ascites / metabolism
  • Ascitic Fluid / metabolism
  • B7-1 Antigen / metabolism
  • B7-2 Antigen / metabolism
  • Bone Marrow Transplantation
  • Cytokines / immunology
  • Extracellular Space / metabolism*
  • Flow Cytometry
  • Gastrointestinal Tract / metabolism
  • Graft vs Host Disease / metabolism*
  • Humans
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Phosphorylation
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / metabolism*
  • STAT1 Transcription Factor / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Whole-Body Irradiation

Substances

  • B7-1 Antigen
  • B7-2 Antigen
  • Cytokines
  • Receptors, Purinergic P2X7
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferon-gamma
  • Adenosine Triphosphate