title: Graft-versus-host disease is enhanced by selective CD73 blockade in mice.
abstract: CD73 functions as an ecto-5'-nucleotidase to produce extracellular adenosine that has anti-inflammatory and immunosuppressive activity. We here demonstrate that CD73 helps control graft-versus-host disease (GVHD) in mouse models. Survival of wild-type (WT) recipients of either allogeneic donor naïve CD73 knock-out (KO) or WT T cells was similar suggesting that donor naïve T cell CD73 did not contribute to GVHD. By contrast, donor CD73 KO CD4(+)CD25(+) regulatory T cells (Treg) had significantly impaired ability to mitigate GVHD mortality compared to WT Treg, suggesting that CD73 on Treg is critical for GVHD protection. However, compared to donor CD73, recipient CD73 is more effective in limiting GVHD. Pharmacological blockade of A2A receptor exacerbated GVHD in WT recipients, but not in CD73 KO recipients, suggesting that A2 receptor signaling is primarily implicated in CD73-mediated GVHD protection. Moreover, pharmacological blockade of CD73 enzymatic activity induced stronger alloreactive T cell activity, worsened GVHD and enhanced the graft-versus-leukemia (GVL) effect. These findings suggest that both donor and recipient CD73 protects against GVHD but also limits GVL effects. Thus, either enhancing or blocking CD73 activity has great potential clinical application in allogeneic bone marrow transplants.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Siqi
authors.initials: S
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000276:immunology*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D016026:Bone Marrow Transplantation; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D020544:Graft vs Leukemia Effect / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D015720:5'-Nucleotidase