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

Area of Science:

• Immunology
• Transplantation Medicine
• Cellular Signaling

Background:

• Cell damage releases danger signals, leading to immune-mediated tissue destruction in conditions like graft-versus-host disease (GVHD).
• Extracellular adenosine triphosphate (ATP) and its receptor P2X7R are implicated in immune cell activation and inflammatory responses.

Purpose of the Study:

• To investigate the role of extracellular ATP as a danger signal in GVHD.
• To evaluate the therapeutic potential of targeting the ATP-P2X7R pathway in transplantation.

Main Methods:

• Measured ATP concentrations in peritoneal fluid during GVHD development in mice and humans.
• Stimulated antigen-presenting cells (APCs) with ATP in vitro and in vivo.
• Assessed the effects of ATP on immune cell activation, cytokine production, and T cell expansion.
• Investigated the impact of ATP neutralization, P2X7R blockade, or genetic deficiency on GVHD outcomes and survival.

Main Results:

• Increased ATP concentrations were observed in GVHD models and human samples.
• ATP stimulation of APCs promoted pro-inflammatory responses, including CD80/CD86 upregulation, STAT1 phosphorylation, and IFN-γ production, while reducing regulatory T cells.
• P2X7R expression increased during GVHD, creating a positive feedback loop.
• Interventions targeting ATP or P2X7R improved survival without inducing immune paralysis.

Conclusions:

• Extracellular ATP acts as a critical danger signal in GVHD, amplifying immune pathology via P2X7R.
• Targeting the ATP-P2X7R axis offers a promising strategy for promoting transplant tolerance without broad immunosuppression.