The selective activation of the A_2A has therapeutic potential in both the prevention and treatment of acute GVHD.

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_2AR 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_2AR 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_2AR has therapeutic potential in the prevention and treatment of acute GVHD.