Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice
Amplification of Regulatory T Cells Using a CD28 Superagonist Reduces Brain Damage After Ischemic Stroke in Mice
复制标题
DOI：
10.1161/strokeaha.114.007756
复制
发表时间：
2015-01-01
期刊：
影响因子：
8.3
通讯作者：
Veltkamp, Roland
中科院分区：
文献类型：
--
作者：
Na, Shin-Young;Mracsko, Eva;Veltkamp, Roland
背景和目的-神经炎症在缺血性脑损伤中起重要作用。调节性T细胞(Treg)是重要的内源性免疫调节剂。我们验证了CD28超激动型单抗(CD28SA)扩增Treg能减轻小鼠脑缺血损伤的假说。方法C57BL6小鼠采用大脑中动脉远端凝固法或大脑中动脉近端细丝结扎60min法诱导脑缺血。脑缺血后3h或6h，腹腔注射CD28SA 150mg.结果通过脑梗塞体积测量和行为学测试来确定。用流式细胞仪和免疫组织化学方法检测脑缺血后3d和7d脑组织中白细胞亚群的变化。结果：CD28SA可缩小两种模型的脑梗塞范围，减轻脑功能障碍。CD28SA处理的小鼠脾和脑中Treg的数量增加。Treg在功能上是活跃的，并迁移到大脑中，在脑梗塞周围区域积聚和增殖。超过60%的脑浸润性Treg在CD28SA中产生IL-10，而对照组为30%。结论：CD28SA体内扩增Treg可减轻实验性卒中后的炎症反应，改善预后。
Background and Purpose-Neuroinflammation plays an important role in ischemic brain injury. Regulatory T cells (Treg) are important endogenous immune modulators. We tested the hypothesis that Treg amplification with a CD28 superagonistic monoclonal antibody (CD28SA) reduces brain damage in murine cerebral ischemia.Methods-Cerebral ischemia was induced by coagulation of the distal middle cerebral artery or by 60 minutes filament occlusion of the proximal middle cerebral artery in C57BL6 mice. 150 mu g CD28SA was injected intraperitoneally 3 or 6 hours after ischemia onset. Outcome was determined by infarct volumetry and behavioral testing. Brain-infiltrating leukocyte subpopulations were analyzed by flow cytometry and immunohistochemistry 3 and 7 days after middle cerebral artery occlusion.Results-CD28SA reduced infarct size in both models and attenuated functional deficit 7 days after stroke induction. Mice treated with CD28SA increased numbers of Treg in spleen and brain. Tregs were functionally active and migrated into the brain where they accumulated and proliferated in the peri-infarct area. More than 60% of brain infiltrating Treg produced interleukin-10 in CD28SA compared with 30% in control.Conclusions-In vivo expansion and amplification of Treg by CD28SA attenuates the inflammatory response and improves outcome after experimental stroke.