Anesthesiology Department of Huashan Hospital, State Key Laboratory of Medical Neurobiology and Institute of Brain Sciences, Fudan University, Shanghai, China; Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Ann Neurol. 2013 Sep;74(3):458-71. doi: 10.1002/ana.23815. Epub 2013 May 14.
Recent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immunomodulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg-afforded neuroprotection.
We examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg-neutrophil cocultures using a combined approach including cell-specific depletion, gene knockout mice, and bone marrow chimeras.
Systemic administration of purified Tregs at 2, 6, or even 24 hours after middle cerebral artery occlusion resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg-afforded neuroprotection was accompanied by attenuated blood-brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation, and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil-derived matrix metallopeptidase-9 production, thus preventing proteolytic damage of the BBB. In addition to its potent central neuroprotection, Treg treatment was shown to ameliorate poststroke lymphopenia, suggesting a beneficial effect on immune status.
Our study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption.
最近的证据表明，调节性 T 细胞（Tregs）作为一种先天免疫调节剂的功能缺陷会加剧脑缺血后的脑损伤。因此，我们评估了 Treg 转移在缺血性卒中啮齿动物模型中的作用，并进一步研究了 Treg 提供神经保护的机制。
我们通过细胞特异性耗竭、基因敲除小鼠和骨髓嵌合体等综合方法，在 2 种缺血性卒中啮齿动物模型体内和 Treg-中性粒细胞共培养物体外，检查了 Tregs 的治疗潜力和神经保护机制。
在大脑中动脉闭塞后 2、6 甚至 24 小时，系统给予纯化的 Tregs 可显著减少脑梗死，并延长至 4 周的神经功能改善。Treg 提供的神经保护伴随着早期缺血时血脑屏障（BBB）破坏的减弱、脑炎症的减少和外周炎症细胞浸润到损伤大脑的减少。令人惊讶的是，Tregs 发挥早期神经保护作用而不穿透脑实质或抑制驻留小胶质细胞的激活。实际上，体内和体外研究均表明，Tregs 抑制外周中性粒细胞衍生的基质金属蛋白酶-9 的产生，从而防止 BBB 的蛋白水解损伤。除了强大的中枢神经保护作用外，Treg 治疗还被证明可改善卒中后淋巴细胞减少症，表明对免疫状态有益。
我们的研究表明，Treg 过继疗法是一种针对卒中后炎症失调和神经血管破坏的新型有效细胞疗法。
