Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice.
Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice.
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DOI：
10.1126/scitranslmed.aao6459
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发表时间：
2018-05-16
影响因子：
17.1
通讯作者：
Tomlinson S
中科院分区：
文献类型：
--
作者：
Alawieh A;Langley EF;Tomlinson S
缺血性中风是由于流向大脑的血流中断导致长期运动和认知神经功能障碍而引起的，它是死亡和残疾的主要原因。目前的干预措施侧重于恢复血流以限制神经元死亡，但这些治疗的治疗窗口只有几个小时，并且不能解决中风后脑炎症。补体系统是先天免疫系统的一个组成部分，由天然免疫球蛋白 M (IgM) 抗体激活，这些抗体识别缺血性中风后大脑中表达的新表位。我们利用这种识别系统来抑制小鼠缺血区域的局部补体激活。中风后，将识别与补体抑制剂相连的缺血后新表位的单链抗体（称为 B4Crry）作为单剂量全身给药，并显示出特异性靶向缺血半球并改善长期运动和认知恢复。我们发现，补体调理素引导小胶质细胞吞噬受应激但可挽救的神经元，并且通过局部和短暂地抑制补体沉积，B4Crry 阻止了半影神经元的吞噬作用，并抑制了病理补体和小胶质细胞的激活，否则这些激活在中风后会持续数周。 B4Crry 对成年、老年、雄性和雌性小鼠均具有保护作用，且治疗窗口期为中风后至少 24 小时。此外，B4Crry 在小鼠中识别的表位在急性中风患者的缺血半暗带中过度表达，但在对侧组织中没有过度表达，这凸显了该方法的转化潜力。
Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke. We took advantage of this recognition system to inhibit complement activation locally in the ischemic area in mice. A single chain antibody recognizing a post-ischemic neoepitope linked to a complement inhibitor (termed B4Crry) was administered systemically as a single dose after stroke and shown to specifically target the ischemic hemisphere and improve long-term motor and cognitive recovery. We show that complement opsonins guide microglial phagocytosis of stressed but salvageable neurons, and that by locally and transiently inhibiting complement deposition, B4Crry prevented phagocytosis of penumbral neurons and inhibited pathologic complement and microglial activation that otherwise persisted for several weeks after stroke. B4Crry was protective in adult, aged, male and female mice and had a therapeutic window of at least 24 hours after stroke. Furthermore, the epitope recognized by B4Crry in mice is overexpressed in the ischemic penumbra of acute stroke patients, but not in the contralateral tissue, highlighting the translational potential of this approach.
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DOI：
10.4049/jimmunol.1102132
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Elvington A;Atkinson C;Kulik L;Zhu H;Yu J;Kindy MS;Holers VM;Tomlinson S
通讯作者：
Tomlinson S
影响因子：
8.3
作者：
Gauthier LV;Taub E;Mark VW;Barghi A;Uswatte G
通讯作者：
Uswatte G
影响因子：
34.7
作者：
Brown, Guy C.;Neher, Jonas J.
通讯作者：
Neher, Jonas J.
影响因子：
5.3
作者：
Alawieh, Ali;Langley, E. Farris;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
影响因子：
158.5
作者：
Hacke, Werner;Kaste, Markku;Toni, Danilo
通讯作者：
Toni, Danilo