Inflammation resolution, neuroprotection, and brain repair to promote stroke recovery

炎症消解、神经保护和大脑修复以促进中风康复

• 批准号: 10261320
• 负责人: Jun Chen
• 金额: $ 40.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261320
• 关键词: 3-Dimensional; Acute; Adoptive Transfer; Adult; Anti-Inflammatory Agents; Autoimmune; B-Lymphocytes; Behavioral; Brain; Brain Diseases; Brain Infarction; Brain Injuries; CD3 Antigens; CD8B1 gene; CXCR3 gene; Cell Culture Techniques; Cell Separation; Cells; Cerebral Ischemia; Cognitive; Data; Deterioration; Development; Diffusion Magnetic Resonance Imaging; Disease; Distal; Dose; Economic Burden; Electron Microscopy; Electrophysiology (science); Encephalitis; Environment; Epidermal Growth Factor; Fostering; Functional disorder; Gender; Genes; Genetic Transcription; Genomics; Harvest; Histologic; Home; Homeostasis; IL2RA gene; IL2RB gene; Imaging Device; Immune; Immune response; Immune system; Immunohistochemistry; Immunomodulators; Immunotherapeutic agent; In Vitro; Infarction; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-10; Ischemia; Ischemic Brain Injury; Ischemic Stroke; LIF gene; LIFR gene; Lead; Light; Lymphocyte; Mediating; Memory; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Names; Nervous System Physiology; Neurologic Deficit; Pathway interactions; Performance; Phase; Pilot Projects; Play; Population; Production; Regulatory T-Lymphocyte; Research; Resolution; Rodent Model; Role; Signal Transduction; Slice; Stroke; T cell therapy; T memory cell; T-Cell Depletion; T-Lymphocyte; Testing; Therapeutic; Transforming Growth Factors; Up-Regulation; aged; brain repair; clinically relevant; clinically translatable; cytokine; functional outcomes; gray matter; immunoregulation; improved; in vivo Model; injury recovery; interest; leukemia inhibitory factor receptor; male; neuroinflammation; neurological recovery; neuroprotection; neurorestoration; novel; novel therapeutic intervention; post stroke; reconstitution; stroke outcome; stroke recovery; stroke therapy; treatment strategy; white matter

Accumulating evidence implicates inflammation and immune responses in the pathophysiology of stroke. Immunomodulation has therefore emerged as a promising therapy for stroke. Regulatory lymphocytes, including CD4+CD25+ regulatory T cells (CD4+ Treg) and IL-10+ regulatory B cells (Bregs) are established modulators of immune responses in the injured brain. We recently discovered that another specialized T cell subpopulation—the CD8+CD122+CD49dhigh regulatory T cell—is among the first to enter the ischemic brain, even preceding the infiltration of CD4+ Tregs and Bregs. The primary function of CD8+ Tregs is to modulate the activities of other immune cells, especially effector T lymphocytes, and to maintain immune homeostasis. We found that selective depletion of circulating CD8+ Tregs exacerbated brain injury and functional outcomes at 3 and 7 days after stroke, and this could be reversed by the reconstitution of CD8+ Tregs. These exciting results suggest that CD8+ Tregs are natural defenders against ischemic brain injury. Further pilot studies discovered that: 1) CD8+ Treg-afforded early protection relies on their infiltration into the ischemic brain, as CD8+ Tregs lacking the “brain targeting signal” CXCR3 do not infiltrate into the ischemic brain and lose their capacity to reduce brain infarction in CD8+ Treg-depleted mice. 2) The infiltrated CD8+ Tregs undergo genomic reprogramming upon brain infiltration and transcriptional upregulation of a group of genes that possess inflammation-resolving and/or neurorestorative functions, including the leukemia inhibitory factor (LIF) receptor and epidermal growth factor-like transforming growth factor (ETGF). 3) Post-stroke adoptive transfer of CD8+ Tregs significantly reduces brain infarct, enhances white matter integrity, and improves neurological functions up to 14d after tMCAO. 4) Adoptive transfer of ETGF-deficient CD8+ Treg fails to protect against tMCAO. The current proposal will further explore the effects of CD8+ Tregs in ischemic stroke and develop CD8+ Treg adoptive transfer as an immune therapeutic therapy for stroke. The novel central hypothesis to be tested is that brain infiltration of CD8+ Tregs promotes long-term neurological recovery after stroke through LIF/LIFR/ETGF-mediated neuroprotection, resolution of neuroinflammation, and neurorestorative mechanisms. Three specific aims are proposed. Aim 1. Establish post-stroke adoptive transfer of CD8+ Tregs as a clinically relevant treatment against acute ischemic brain infarct. Aim 2. Test the hypothesis that post-stroke adoptive transfer of CD8+ Tregs promotes long-term neurological recovery and neurorestoration after ischemic stroke. Aim 3. Test the hypothesis that LIF/LIFR-mediated release of ETGF is essential for CD8+ Treg-afforded neuroprotection and neurorestoration. This study will be the first to rigorously investigate the role of CD8+ Tregs in ischemic brain injury. The results will improve our understanding of stroke immunomodulation and shed light on CD8+ Treg transfer as a potential therapeutic strategy.

越来越多的证据表明，炎症和免疫反应在炎症的病理生理学中起着重要作用。 中风因此，免疫调节已成为一种有前途的治疗中风。监管 淋巴细胞，包括CD 4 + CD 25+调节性T细胞（CD 4 + Treg）和IL-10+调节性B细胞（BCRs）， 在受伤的大脑中建立了免疫反应的调节器。我们最近发现另一个 一种特殊的T细胞亚群--CD 8 + CD 122 + CD 49 dhigh调节性T细胞--是最早进入免疫系统的细胞之一。 缺血脑组织中CD 4 + T淋巴细胞和Bcl-2的浸润早于缺血脑组织中的T淋巴细胞和Bcl-2的浸润。CD 8+的主要功能 T淋巴细胞是调节其他免疫细胞，特别是效应T淋巴细胞的活动，并维持 免疫稳态我们发现循环中CD 8 + T淋巴细胞的选择性耗竭会加重脑损伤， 在中风后3天和7天的功能结果，这可以通过重建 CD 8 + T细胞。这些令人兴奋的结果表明，CD 8 + T细胞是缺血性脑损伤的天然防御者。 损伤进一步的初步研究发现：1）CD 8 + Treg的早期保护作用依赖于其浸润 由于缺乏“脑靶向信号”CXCR 3的CD 8 + T细胞不能浸润到缺血性脑中， 在CD 8 + Treg缺失小鼠中，它们可以减少缺血性脑并失去减少脑梗死的能力。2)的 浸润的CD 8 + T细胞在脑浸润和转录后经历基因组重编程 上调一组具有炎症消退和/或神经恢复功能的基因， 包括白血病抑制因子（LIF）受体和表皮生长因子样转化生长因子 因子（ETGF）。3)脑卒中后过继转移CD 8 + T细胞显著减少脑梗死， 白色物质的完整性，并改善神经功能长达14天后tMCAO。4)的过继转移 ETGF缺陷型CD 8 + Treg不能保护tMCAO。目前的建议将进一步探讨 CD 8 + Treg过继转移作为免疫治疗方法 治疗中风有待检验的新的中心假设是，CD 8 + T细胞的脑浸润促进了 通过LIF/LIFR/ETGF介导的神经保护作用， 神经炎症和神经修复机制。提出了三个具体目标。目标1.建立 脑卒中后过继转移CD 8 + T细胞作为急性缺血性脑损伤的临床相关治疗 梗塞目标2.检验卒中后过继转移CD 8 + T细胞是否促进长期的 缺血性卒中后的神经恢复和神经修复。目标3.测试的假设 LIF/LIFR介导的ETGF释放对于CD 8 + Treg提供的神经保护作用是必需的， 神经修复这项研究将是第一个严格研究CD 8 + T细胞在缺血性脑损伤中的作用的研究。 损伤这些结果将有助于我们对中风免疫调节的理解，并阐明CD 8 + Treg 转移作为一种潜在的治疗策略。