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

摘要

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 ). 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.