Regulatory T cell as a restorative therapy for ischemic stroke

调节性 T 细胞作为缺血性中风的恢复疗法

• 批准号: 9237323
• 负责人: Xiaoming Hu
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237323
• 关键词: Acute; Adoptive Transfer; Aftercare; Animals; Antibodies; Biological Preservation; Blood Circulation; Brain; Brain Injuries; Cell Differentiation process; Cell Proliferation; Cells; Cerebral Ischemia; Cessation of life; Clinical; Clinical Trials; Complex; Data; Environment; Failure; Generations; IL2RA gene; Immune response; Immunotherapy; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injection of therapeutic agent; Interleukin-10; Interleukin-2; Ischemia; Ischemic Stroke; Knockout Mice; Lesion; Measures; Microglia; Middle Cerebral Artery Occlusion; Modeling; Myelin; Myelin Sheath; Neurological outcome; Oligodendroglia; Outcome; Phenotype; Prevention; Production; Recovery; Recovery of Function; Regulatory T-Lymphocyte; Reperfusion Therapy; Research; Role; Sensorimotor functions; Stroke; T-Lymphocyte; Testing; Therapeutic Studies; Tissues; aged; behavior test; cytokine; disability; functional disability; functional outcomes; gray matter; immunoregulation; improved; in vivo; inflammatory marker; injured; injury and repair; macrophage; neurological recovery; neuroprotection; neurovascular; novel; novel strategies; oligodendrocyte precursor; post stroke; precursor cell; public health relevance; repaired; restoration; stroke recovery; tissue repair; white matter; white matter injury; young adult

 DESCRIPTION (provided by applicant): White matter (WM) lesions, characterized by the loss of myelin and myelin-producing oligodendrocytes (OLs), are a major cause of functional disability after stroke but have not been widely appreciated in therapeutic studies until recently. Here we propose to rectify this gap in the field by focusing on WM integrity and its modulation by immune responses in the ischemic brain. Activated microglia/macrophages of distinct phenotypes are known to determine OL cell fate and WM integrity after brain injuries. Specifically, the "alternatively activated" M2 phenotype is essential for WM preservation and repair because M2 cells resolve local inflammation, clear broken myelin sheaths, and provide trophic factors that promote WM repair. CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells that negatively regulate immune responses. Our recent study demonstrated that adoptive Treg therapy exerted early neuroprotection by targeting inflammatory dysregulation and neurovascular disruption after stroke. However, it is not known whether Tregs also have a beneficial effect on WM integrity. Recently, we discovered that Treg-conditioned media stimulates microglial polarization toward the M2 phenotype, and M2 microglia enhance OL survival and promote OPC differentiation in vitro. These exciting results suggest that Tregs can preserve WM integrity. We obtained further promising data showing that 1) Treg transfer at 2h of reperfusion reduced the extent of WM injury and improved sensorimotor functions for at least 28d after transient middle cerebral artery occlusion (tMCAO); 2) Post-stroke Treg treatment resulted in a long-lasting elevation of IL-10, a major Treg-derived cytokine that is important for WM repair; 3) Treg treatment promoted M2 polarization of microglia/macrophages in both WM and gray matter after tMCAO. Furthermore, we have successfully induced a robust increase of Tregs in the circulation after stroke by systemic injection of interleukin (IL)-2/IL-2 antibody complex (IL-2/IL- 2Ab), an established approach to expand Tregs in vivo. We demonstrated that IL-2/IL-2Ab-induced Treg expansion reduces myelin loss 7d after tMCAO and improves sensorimotor functions. The current proposal will further explore the effects of Tregs on WM injury and repair after stroke and develop in vivo Treg expansion as a novel strategy to promote WM integrity and enhance post-stroke recovery. The central hypothesis to be tested is that Tregs promote WM integrity and long-term recovery after stroke by polarizing microglia/macrophages toward the M2 phenotype in an IL-10 dependent manner. Three specific aims are proposed: Aim 1. Test the hypothesis that Treg treatment after stroke improves long-term functional recovery and promotes WM integrity. Aim 2. Test the hypothesis that Treg-derived IL-10 shifts microglia/macrophage polarization towards the M2 phenotype, thereby promoting WM integrity after stroke. Aim 3. Test the hypothesis that in vivo expansion of Tregs with post-stroke IL-2/IL-2Ab treatment is effective in reducing long-term WM injury and improving neurological recovery after stroke.

 描述（由申请人提供）：白质（WM）病变以髓磷脂和产生髓磷脂的少突胶质细胞（OL）损失为特征，是中风后功能障碍的主要原因，但直到最近才在治疗研究中得到广泛认识。 在这里，我们建议通过关注缺血性大脑中 WM 完整性及其免疫反应的调节来纠正这一领域的空白，已知不同表型的激活的小胶质细胞/巨噬细胞决定脑损伤后 OL 细胞的命运和 WM 完整性。 “选择性激活”M2 表型对于 WM 保存和修复至关重要，因为 M2 细胞可以解决局部炎症、清除破损的髓鞘并提供促进 WM 修复的营养因子。 CD4+CD25+ 调节性 T 细胞 (Treg) 是一种特殊的 T 细胞亚群，可负向调节免疫反应，过继性 Treg 疗法通过针对中风后的炎症失调和神经血管破坏发挥早期神经保护作用。最近，我们发现 Treg 条件培养基刺激小胶质细胞向 M2 表型极化，并且 M2 小胶质细胞增强 OL 存活并促进 OPC 分化。这些令人兴奋的结果表明，Treg 可以保持 WM 完整性，表明 1) 再灌注 2 小时时 Treg 转移可减轻 WM 损伤程度，并在短暂大脑中动脉闭塞 (tMCAO) 后至少 28 天内改善感觉运动功能。 )；2) 中风后 Treg 治疗导致 IL-10 持续升高，IL-10 是一种主要的 Treg 衍生细胞因子，对 WM 修复很重要；3) Treg 治疗促进 M2 极化；此外，我们通过全身注射白细胞介素 (IL)-2/IL-2 抗体复合物 (IL-2/) 成功诱导中风后循环中 Treg 的强劲增加。 IL-2Ab），一种体内扩增 Treg 的既定方法，我们证明 IL-2/IL-2Ab 诱导的 Treg 扩增可减少 tMCAO 后 7 天的髓磷脂损失，并改善感觉运动功能。将进一步探索Tregs对中风后WM损伤和修复的影响，并开发体内Treg扩增作为促进WM完整性和增强中风后恢复的新策略。要测试的中心假设是Tregs促进WM完整性和长期恢复。通过以 IL-10 依赖性方式将小胶质细胞/巨噬细胞极化向 M2 表型来实现中风后的足月恢复，提出了三个具体目标： 目标 1. 检验中风后 Treg 治疗可改善长期功能恢复并促进 WM 完整性的假设。目标 2. 检验 Treg 衍生的 IL-10 将小胶质细胞/巨噬细胞极化转向 M2 表型，从而促进中风后 WM 完整性的假设。 目标 3. 检验中风后 IL-2/Treg 体内扩增的假设。 IL-2Ab 治疗可有效减少长期 WM 损伤并改善中风后的神经功能恢复。