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The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease.
Clin Exp Immunol. 2017 10; 190(1):79-95.CE

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)-2Rγnull (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+Show Affiliations

School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.Sydney Medical School Nepean, University of Sydney, Nepean Hospital, Penrith, NSW, Australia.Sydney Medical School Westmead, University of Sydney, Westmead Hospital, NSW, Australia. Institute for Clinical Pathology and Medical Research, Westmead, NSW Health Pathology, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.Children's Hospital at Westmead, Westmead, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia. Centre for Medical and Molecular Biosciences, University of Wollongong, Wollongong, NSW, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28665482

Citation

Geraghty, N J., et al. "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, vol. 190, no. 1, 2017, pp. 79-95.
Geraghty NJ, Belfiore L, Ly D, et al. The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease. Clin Exp Immunol. 2017;190(1):79-95.
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. https://doi.org/10.1111/cei.13005
Geraghty NJ, et al. The P2X7 Receptor Antagonist Brilliant Blue G Reduces Serum Human Interferon-γ in a Humanized Mouse Model of Graft-versus-host Disease. Clin Exp Immunol. 2017;190(1):79-95. PubMed PMID: 28665482.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease. AU - Geraghty,N J, AU - Belfiore,L, AU - Ly,D, AU - Adhikary,S R, AU - Fuller,S J, AU - Varikatt,W, AU - Sanderson-Smith,M L, AU - Sluyter,V, AU - Alexander,S I, AU - Sluyter,R, AU - Watson,D, Y1 - 2017/07/24/ PY - 2017/06/23/accepted PY - 2017/7/1/pubmed PY - 2017/10/4/medline PY - 2017/7/1/entrez KW - Brilliant Blue G KW - P2X7 receptor KW - bone marrow transplantation KW - graft-versus-host disease KW - humanized mice KW - lymphocyte KW - purinergic signalling SP - 79 EP - 95 JF - Clinical and experimental immunology JO - Clin. Exp. Immunol. VL - 190 IS - 1 N2 - 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)-2Rγnull (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. SN - 1365-2249 UR - https://www.unboundmedicine.com/medline/citation/28665482/The_P2X7_receptor_antagonist_Brilliant_Blue_G_reduces_serum_human_interferon_γ_in_a_humanized_mouse_model_of_graft_versus_host_disease_ L2 - https://doi.org/10.1111/cei.13005 DB - PRIME DP - Unbound Medicine ER -