Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation
Adenosine A2A receptor activation limits graft-versus-host disease after allogenic hematopoietic stem cell transplantation
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DOI：
10.1189/jlb.0609388
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发表时间：
2010-02-01
影响因子：
5.5
通讯作者：
Malech, Harry L.
中科院分区：
文献类型：
--
作者：
Lappas, Courtney M.;Liu, Po-Ching;Malech, Harry L.
移植物抗宿主病是广泛应用同种异体造血干细胞移植治疗原发性免疫缺陷和血红蛋白病的主要障碍。我们在C57 BL/6 J（H2-k（B））-> B6 D2 F1/J（H2-k（B/d））急性GVHD的鼠模型中显示，当在移植前2天开始时，用选择性激动剂ATL 146 e激活腺苷A（2A）R抑制与疾病进展相关的体重减轻和死亡率。此外，经过14天的ATL 146 e治疗，促炎细胞因子和趋化因子（包括IFN-γ、IL-6、CCL 2、KC和G-CSF）的循环水平显着降低。供体CD 4（+）和CD 8（+）T细胞对CD 25、CD 69和CD 40 L表达的上调受到A（2A）R活化的抑制;与溶剂处理对照组相比，在ATL 146 e处理小鼠的肝脏、皮肤和结肠中发现较少的CD 3（+）T细胞;相关组织损伤减轻。在HSCT后9天开始延迟给予ATL 146 e，成功逆转了GVHD相关的体重减轻，并且在治疗期间持续改善。我们的结论是选择性激活A2 AR在预防和治疗急性GVHD的治疗潜力。J. Leukoc. 87：345-354; 2010.
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-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 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 A2AR has therapeutic potential in the prevention and treatment of acute GVHD. J. Leukoc. Biol. 87: 345-354; 2010.