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Originally published online as doi:10.1189/jlb.0609388 on November 4, 2009

Published online before print November 4, 2009
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(Journal of Leukocyte Biology. 2010;87:345-354.)
© 2010 Society for Leukocyte Biology

Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation

Courtney M. Lappas*,1, Po-Ching Liu{dagger}, Joel Linden{ddagger}, Elizabeth M. Kang{dagger} and Harry L. Malech{dagger}

* Department of Biology, Lebanon Valley College, Annville, Pennsylvania, USA;
{dagger} National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; and
{ddagger} Department of Medicine, University of Virginia, Charlottesville, Virginia, USA

1. Correspondence: Lebanon Valley College, Neidig-Garber 313, 101 North College Ave., Annville, PA 17003, USA. E-mail: lappas{at}lvc.edu

ABSTRACT

GVHD is a major barrier to broader use of allogenic HSCT for nonmalignancy clinical applications such as the treatment of primary immunodeficiencies and hemoglobinopathies. We show in a murine model of C57BL/6J (H2-kb) -> B6D2F1/J (H2-kb/d) acute GVHD that when initiated 2 days before transplant, the activation of the adenosine A2AR with the selective agonist ATL146e inhibits the weight loss and mortality associated with disease progression. Furthermore, circulating levels of proinflammatory cytokines and chemokines, including IFN-{gamma}, IL-6, CCL2, KC, and G-CSF, are reduced significantly by 14-day ATL146e treatment. The up-regulation of CD25, CD69, and CD40L expression by donor CD4+ and CD8+ T cells is inhibited by A2AR activation; fewer CD3+ T cells are found in the liver, skin, and colon of ATL146e-treated mice as compared with vehicle-treated controls; and associated tissue injury is lessened. The delayed administration of ATL146e, beginning 9 days after HSCT, reverses GVHD-associated body weight loss successfully, and improvement is sustained for the duration of treatment. We conclude that the selective activation of the A2AR has therapeutic potential in the prevention and treatment of acute GVHD.

Key Words: T lymphocytes • inflammation • immunodeficiency