Activation of the adenosine A2A receptor attenuates experimental autoimmune myasthenia gravis severity
Activation of the adenosine A2A receptor attenuates experimental autoimmune myasthenia gravis severity
复制标题
腺苷 A2A 受体的激活可减轻实验性自身免疫性重症肌无力的严重程度
DOI：
10.1002/eji.201142088
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发表时间：
2012-05-01
影响因子：
5.4
通讯作者：
Li, Hulun
中科院分区：
文献类型：
--
作者：
Li, Na;Mu, Lili;Li, Hulun
腺苷A2 A受体（A2 AR）是通常与免疫抑制相关的主要细胞腺苷受体。在这里，我们研究了A2 AR激活是否具有影响用乙酰胆碱受体（AChR）R97-116肽免疫刘易斯大鼠后诱导的实验性自身免疫性重症肌无力（EAMG）严重程度的潜力。本报告证实了EAMG诱导后脾和淋巴结中T细胞和B细胞的A2 AR表达降低。A2 AR刺激抑制体外AChR特异性淋巴细胞的抗AChR抗体产生和增殖。用A2 AR拮抗剂或蛋白激酶A抑制剂阻断抑制。我们还确定EAMG的发展伴随着辅助性T细胞失衡，这种失衡可以在A2 AR刺激后恢复，导致Treg细胞水平增加和Th 1-，Th 2-和Th 17-细胞亚型减少。建立了EAMG预防性治疗方案，包括在EAMG诱导前1天给予（2-（对-（2-羰基乙基）苯乙基氨基）-5-N-乙基甲酰氨基腺苷）（CGS 21680; A2 AR激动剂）。EAMG诱导（治疗性处理）后29天给予CGS 21680也改善了疾病严重程度。我们得出结论，A2 AR激动剂可能代表一类新的化合物，可开发用于治疗重症肌无力或其他T细胞和B细胞介导的自身免疫性疾病。
The adenosine A2A receptor (A2AR) is the major cellular adenosine receptor commonly associated with immunosuppression. Here, we investigated whether A2AR activation holds the potential for impacting the severity of experimental autoimmune myasthenia gravis (EAMG) induced following immunization of Lewis rats with the acetylcholine receptor (AChR) R97–116 peptide. This report demonstrates reduced A2AR expression by both T cells and B cells residing in spleen and lymph nodes following EAMG induction. A2AR stimulation inhibited anti‐AChR antibody production and proliferation of AChR‐specific lymphocytes in vitro. Inhibition was blocked with the A2AR antagonists or protein kinase A inhibitor. We also determined that the development of EAMG was accompanied by a T‐helper cell imbalance that could be restored following A2AR stimulation that resulted in increased Treg cell levels and a reduction in Th1‐, Th2‐, and Th17‐cell subtypes. An EAMG‐preventive treatment regimen was established that consisted of (2‐(p‐(2‐carbonylethyl)phenylethylamino)‐5‐N‐ethylcarboxamidoadenosine) (CGS21680; A2AR agonist) administration 1 day prior to EAMG induction. Administration of CGS21680 29 days post EAMG induction (therapeutic treatment) also ameliorated disease severity. We conclude that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of myasthenia gravis or other T‐cell‐ and B‐cell‐mediated autoimmune diseases.