Extracellular adenosine is a therapeutic target for limiting graft-versus-host disease and enhancing the graft-versus-tumor effect against hematopoietic malignancy

Hiroki Tsukamoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Allogeneic hematopoietic stem cell transplantation is performed in patients with hematologic malignancies refractory to chemotherapy. However, its e‹cacy is often limited by the development of graft-versus-host disease (GVHD) secondary to the allogeneic interaction of donor T cells with host dendritic cells. On the other hand, the antihost cytotoxicity of donor T cells enhances the graft-versus-tumor (GVT) effect. Extracellular adenosine generated by CD73/ecto-5′-nucleotidase from ATP via AMP plays pleiotropic roles under physiological and pathological conditions by engaging four adenosine receptors. One study recently demonstrated that ATP released from damaged cells exacerbates GVHD by activating the P2X7receptor on host dendritic cells. In this review, we summarize our recent findings on the immunosuppressive role of extracellular adenosine in GVHD and the GVT effect. We have shown that in MHC-mismatched bone marrow transplantation, CD73 deficiency, particularly in the recipient, enhanced GVHD severity because of excessive donor T-cell expansion. Severe GVHD was enhanced by repeated administration of a CD73 inhibitor or an adenosine receptor antagonist. A competitive engraftment assay identified endogenous A2AAR signaling in donor T cells as part of a regulatory mechanism by CD73-generated adenosine. Pharmacological inhibition of CD73 enhanced the GVT effect against B-cell lymphoma and improved survival in tumor-relapsing mice after transplantation. Along with our findings, we herein introduce a novel concept that CD73-generated adenosine counteracts the ATP-evoked allogeneic immune reaction as a negative regulatory mechanism in GVHD. Pharmacological manipulation of CD73 activity could be a therapeutic strategy to limit GVHD and to preserve the GVT effect against hematopoietic malignancy.

Original languageEnglish
Pages (from-to)1021-1027
Number of pages7
JournalYakugaku Zasshi
Volume134
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

Keywords

  • Adenosine
  • Adenosine receptoris
  • CD73
  • Ecto-5′-nucleotidase
  • Graft-versus-host disease
  • Graft-versus-tumor effect

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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