The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease

Authors

Nicholas Geraghty, University of WollongongFollow
Lisa Belfiore, University of WollongongFollow
Diane T. Ly, University of WollongongFollow
Sam Adhikary, University of WollongongFollow
Stephen J. Fuller, University of Sydney
W Varikatt, University of Sydney, NSW Health Pathology
Martina L. Sanderson-Smith, University of WollongongFollow
Vanessa Sluyter, University of Wollongong
Stephen I. Alexander, Children's Hospital, WestmeadFollow
Ronald Sluyter, University of WollongongFollow
Debbie Watson, University of WollongongFollow

RIS ID

116423

Publication Details

Geraghty, N. J., Belfiore, L., Ly, D., Adhikary, S. R., Fuller, S. J., Varikatt, W., Sanderson-Smith, M. L., Sluyter, V., Alexander, S. I., Sluyter, R. & Watson, D. (2017). The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease. Clinical and Experimental Immunology, 190 (1), 79-95.

Abstract

Graft-versus-host disease (GVHD) remains a major problem after allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. Previous studies have demonstrated a role for the adenosine triphosphate (ATP)-gated P2X7 receptor channel in allogeneic mouse models of GVHD. In this study, injection of human peripheral blood mononuclear cells (PBMCs) into immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (NOD-SCID-IL)-2Rγ^null (NSG) mice established a humanized mouse model of GVHD. This model was used to study the effect of P2X7 blockade in this disease. From five weeks post-PBMC injection, humanized mice exhibited clinical signs and histopathology characteristic of GVHD. The P2X7 antagonist, Brilliant Blue G (BBG), blocked ATP-induced cation uptake into both murine and human cells in vitro. Injection of BBG (50 mg/kg) into NSG mice did not affect engraftment of human leucocytes (predominantly T cells), or the clinical score and survival of mice. In contrast, BBG injection reduced circulating human interferon (IFN)-γ significantly, which was produced by human CD4⁺ and CD8⁺ T cells. BBG also reduced human T cell infiltration and apoptosis in target organs of GVHD. In conclusion, the P2X7 antagonist BBG reduced circulating IFN-γ in a humanized mouse model of GVHD supporting a potential role for P2X7 to alter the pathology of this disease in humans.