Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 97, Issue 6, Pages 597-610Publisher
WILEY
DOI: 10.1111/imcb.12251
Keywords
Adenosine receptor; CD39; CD73; graft-versus-host disease; invariant natural killer T cells; purinergic receptor; regulatory T cells; T lymphocyte; xenogeneic mice
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Funding
- Faculty of Science, Medicine and Health, University of Wollongong
- AMP Tomorrow Fund
- Molecular Horizons, University of Wollongong
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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 gamma(null) mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist alpha beta-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-alpha). 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.
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