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-k b ) → B6D2F1/J (H2-k b/d ) acute GVHD that when initiated 2 days before transplant, the activation of the adenosine A 2A R 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-γ, 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 A 2A R 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 A 2A R has therapeutic potential in the prevention and treatment of acute GVHD.
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Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation
Lappas, Courtney M.; Liu, Po-Ching; Linden, Joel; Kang, Elizabeth M.; Malech, Harry L.
Follow Journal of Leukocyte Biology
, Volume 87 (2): 345
Fed of American Socs for Experimental Biology – Feb 1, 2010
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