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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.

Authors
  • Geraghty, Nicholas J1, 2, 3
  • Watson, Debbie1, 2, 3
  • Sluyter, Ronald1, 2, 3
  • 1 School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, 2252, Australia. , (Australia)
  • 2 Molecular Horizons, University of Wollongong, Wollongong, NSW, 2252, Australia. , (Australia)
  • 3 Illawarra Health and Medical Research Institute, Wollongong, NSW, 2252, Australia. , (Australia)
Type
Published Article
Journal
Immunology and Cell Biology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jul 01, 2019
Volume
97
Issue
6
Pages
597–610
Identifiers
DOI: 10.1111/imcb.12251
PMID: 30957314
Source
Medline
Keywords
Language
English
License
Unknown

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. © 2019 Australian and New Zealand Society for Immunology Inc.

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