Skip to main content
placeholder image

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

Journal Article


Download full-text (Open Access)

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.

Authors


  •   Geraghty, Nicholas (external author)
  •   Belfiore, Lisa (external author)
  •   Ly, Diane T.
  •   Adhikary, Sam (external author)
  •   Fuller, Stephen J. (external author)
  •   Varikatt, W (external author)
  •   Sanderson-Smith, Martina L.
  •   Sluyter, Vanessa (external author)
  •   Alexander, Stephen I. (external author)
  •   Sluyter, Ronald
  •   Watson, Debbie

Publication Date


  • 2017

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85028988872

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2146&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1120

Has Global Citation Frequency


Number Of Pages


  • 16

Start Page


  • 79

End Page


  • 95

Volume


  • 190

Issue


  • 1

Place Of Publication


  • United Kingdom

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.

Authors


  •   Geraghty, Nicholas (external author)
  •   Belfiore, Lisa (external author)
  •   Ly, Diane T.
  •   Adhikary, Sam (external author)
  •   Fuller, Stephen J. (external author)
  •   Varikatt, W (external author)
  •   Sanderson-Smith, Martina L.
  •   Sluyter, Vanessa (external author)
  •   Alexander, Stephen I. (external author)
  •   Sluyter, Ronald
  •   Watson, Debbie

Publication Date


  • 2017

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85028988872

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2146&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1120

Has Global Citation Frequency


Number Of Pages


  • 16

Start Page


  • 79

End Page


  • 95

Volume


  • 190

Issue


  • 1

Place Of Publication


  • United Kingdom