Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells
Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells
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DOI：
10.1038/bjp.2008.23
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发表时间：
2008-03-01
影响因子：
7.3
通讯作者：
Ohta, A.
中科院分区：
文献类型：
--
作者：
Sitkovsky, M.;Lukashev, D.;Ohta, A.
宿主反应的强度和持续时间由通过抑制炎症来控制组织损伤的保护机制决定。腺苷的产生和随后的效应，通过A2 A腺苷受体（A2 AR）介导的效应细胞，在这些反应的病理生理调节在体内发挥关键作用。腺苷既由缺氧细胞/组织释放，也由胞外酶e. G. CD 39（ENTPD 1）和CD 73，其由脉管系统和免疫细胞，特别是由T调节细胞表达。一般而言，这些腺苷能机制在炎症反应过程中使对宿主组织的附带损伤程度最小化。然而，抑制途径的诱导也可能导致病原体逃逸并允许传播。此外，腺苷能反应可抑制免疫反应，同时增强对促进肿瘤生长的恶性细胞的血管生成反应。阻断A2 AR-腺苷能作用和/或腺苷生成的新药具有促进病原体破坏和选择性破坏恶性组织的潜力。在后一种情况下，未来的治疗方式可能包括新的“抗腺苷能”方法，增加恶性细胞的免疫清除和阻断允许的血管生成。本文综述了几种可能的药理学方法来阻断腺苷能途径，并推测其未来的应用以及对人类疾病的影响。
The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e. g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel 'anti-adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block adenosinergic pathways and speculates on their future application together with impacts on human disease.