Pharmacological blockade of the CD 39/ CD 73 pathway but not adenosine receptors augments disease in a humanized mouse model of graft‐ versus ‐host disease

• Published in: Immunology and cell biology Vol. 97; no. 6; pp. 597 - 610
• Main Authors: Geraghty, Nicholas J, Watson, Debbie, Sluyter, Ronald
• Format: Journal Article
• Language: English
• Published: 01-07-2019
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1111/imcb.12251

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
).
CD
39 and
CD
73 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
CD
39/
CD
73 pathway and adenosine receptor (
AR
) blockade in a humanized mouse model of
GVHD
. Immunodeficient nonobese diabetic‐severe combined immunodeficiency‐
IL
‐2 receptor γ
null
mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the
CD
39/
CD
73 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
CD
4
+
and
CD
8
+
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
(
CD
39/
CD
73 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
CD
39
−

CD
73
−

CD
4
+
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
CD
39/
CD
73 but not
AR
s augments disease in a humanized mouse model of
GVHD
. These results indicate that
CD
39/
CD
73 blockade maintains sufficient extracellular
ATP
concentrations to promote
GVHD
in this model.