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Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft-versus-host disease.
Immunol Cell Biol. 2019 07; 97(6):597-610.IC

Abstract

Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft-versus-host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5'-triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic-severe combined immunodeficiency-IL-2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ-methylene-ADP (APCP) (50 mg kg-1) or saline for 7 days, or the AR antagonist caffeine (10 mg kg-1) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T-cell infiltration, and increased apoptosis. This treatment also increased serum human IL-2 concentrations and decreased the frequency of human CD39- CD73- CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL-2, IL-6, IL-10 or tumor necrosis factor-α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model.

Authors+Show Affiliations

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2252, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2252, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2252, Australia.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2252, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2252, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2252, Australia.School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2252, Australia. Molecular Horizons, University of Wollongong, Wollongong, NSW, 2252, Australia. Illawarra Health and Medical Research Institute, Wollongong, NSW, 2252, Australia.

Pub Type(s)

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

Language

eng

PubMed ID

30957314

Citation

Geraghty, Nicholas J., et al. "Pharmacological Blockade of the CD39/CD73 Pathway but Not Adenosine Receptors Augments Disease in a Humanized Mouse Model of Graft-versus-host Disease." Immunology and Cell Biology, vol. 97, no. 6, 2019, pp. 597-610.
Geraghty NJ, Watson D, Sluyter R. Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft-versus-host disease. Immunol Cell Biol. 2019;97(6):597-610.
Geraghty, N. J., Watson, D., & Sluyter, R. (2019). Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft-versus-host disease. Immunology and Cell Biology, 97(6), 597-610. https://doi.org/10.1111/imcb.12251
Geraghty NJ, Watson D, Sluyter R. Pharmacological Blockade of the CD39/CD73 Pathway but Not Adenosine Receptors Augments Disease in a Humanized Mouse Model of Graft-versus-host Disease. Immunol Cell Biol. 2019;97(6):597-610. PubMed PMID: 30957314.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological blockade of the CD39/CD73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft-versus-host disease. AU - Geraghty,Nicholas J, AU - Watson,Debbie, AU - Sluyter,Ronald, Y1 - 2019/04/29/ PY - 2018/06/15/received PY - 2019/02/28/revised PY - 2019/04/03/revised PY - 2019/04/04/accepted PY - 2019/4/9/pubmed PY - 2020/4/4/medline PY - 2019/4/9/entrez KW - Adenosine receptor KW - CD39 KW - CD73 KW - T lymphocyte KW - graft-versus-host disease KW - invariant natural killer T cells KW - purinergic receptor KW - regulatory T cells KW - xenogeneic mice SP - 597 EP - 610 JF - Immunology and cell biology JO - Immunol. Cell Biol. VL - 97 IS - 6 N2 - Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft-versus-host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5'-triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic-severe combined immunodeficiency-IL-2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ-methylene-ADP (APCP) (50 mg kg-1) or saline for 7 days, or the AR antagonist caffeine (10 mg kg-1) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T-cell infiltration, and increased apoptosis. This treatment also increased serum human IL-2 concentrations and decreased the frequency of human CD39- CD73- CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL-2, IL-6, IL-10 or tumor necrosis factor-α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model. SN - 1440-1711 UR - https://www.unboundmedicine.com/medline/citation/30957314/Pharmacological_blockade_of_the_CD39/CD73_pathway_but_not_adenosine_receptors_augments_disease_in_a_humanized_mouse_model_of_graft_versus_host_disease_ L2 - https://doi.org/10.1111/imcb.12251 DB - PRIME DP - Unbound Medicine ER -