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（由适用提供）：白质（WM）病变，其特征是髓磷脂和产生髓磷脂的少突胶质细胞（OLS）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理解。 在这里，我们建议通过关注WM完整性及其通过缺血性大脑中的免疫反应调节来纠正该领域的这一差距。已知不同表型的活化的小胶质细胞/巨噬细胞确定脑损伤后OL细胞命运和WM完整性。具体而言，“替代激活”的M2表型对于WM制备和修复至关重要，因为M2细胞可以解决局部感染，清除骨髓骨蛋白的鞘裂以及提供促进WM修复的营养因子。 CD4+ CD25+调节T细胞（Tregs）是对T细胞的专门亚群，对免疫回应负面调节。我们最近的研究表明，通过靶向炎症性失调和中风后神经血管破坏，采用的Treg疗法执行了早期神经保护作用。但是，尚不清楚Tregs是否对WM完整性也具有有益的作用。最近，我们发现Treg条件的培养基刺激了针对M2表型的小胶质细化极化，而M2小胶质细胞可增强OL存活并促进体外OPC分化。这些令人兴奋的结果表明Tregs可以保留WM的完整性。我们获得了进一步的承诺数据，表明1）在再灌注2小时的Treg转移降低了WM损伤的程度，并改善了瞬态中大脑动脉闭塞后至少28D的感觉运动功能（TMCAO）；中风后Treg治疗导致IL-10的持久升高，IL-10是Treg衍生的主要细胞因子，对WM修复很重要。 3）Treg处理促进了TMCAO后WM和灰质中的小胶质细胞/巨噬细胞的M2极化。此外，通过全身注射白介素（IL）-2/IL-2抗体复合物（IL-2/IL-2AB），我们成功地诱导了中风后循环中Treg的稳健增加，这是一种在体内扩展Treg的既定方法。我们证明了IL-2/IL-2Ab诱导的Treg膨胀可在TMCAO后降低髓磷脂损失7D并改善感觉运动功能。当前的建议将进一步探讨Tregs对中风后WM损伤和修复的影响，并在体内Treg扩展中发展为一种新的策略，以促进WM完整性并增强冲程后恢复。要测试的中心假设是，Tregs以IL-10依赖性方式通过极化小胶质细胞/巨噬细胞向M2表型促进了WM完整性和长期恢复。提出了三个具体目的：目标1。检验以下假设：Treg衍生的IL-10将小胶质细胞/巨噬细胞极化向M2表型转移，从而促进了中风后的WM完整性。 AIM 3。检验以下假设：中风后IL-2/IL-2AB治疗的体内扩展有效减少长期WM损伤并改善中风后神经系统恢复。