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: 9471926
• 负责人: Jun Chen
• 金额: $ 40.75万
• 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/9471926
• 关键词: Acute; Adoptive Cell Transfers; Adoptive Transfer; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Process; 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); Employee Strikes; Encephalitis; Environment; Epidermal Growth Factor; Fostering; Functional disorder; Gender; Genes; Genetic Transcription; Genomics; Harvest; Histologic; Home environment; Homeostasis; IL2RA gene; IL2RB gene; Imaging Device; Immune; Immune response; Immune system; Immunohistochemistry; 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; Outcome; Pathway interactions; Performance; Phase; Pilot Projects; Play; Population; Production; Recovery; Regulatory T-Lymphocyte; Research; Resolution; Rodent Model; Role; Signal Transduction; Slice; Stroke; T memory cell; 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; interest; leukemia inhibitory factor receptor; male; neuroinflammation; neurological recovery; neuroprotection; neurorestoration; novel; novel therapeutics; post stroke; reconstitution; 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与脑血管病的病理生理学有关 卒中。因此，免疫调节疗法已成为治疗中风的一种很有前途的疗法。监管 淋巴细胞，包括CD4+CD25+调节性T细胞(CD4+Treg)和IL-10+调节性B细胞(Bregs) 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 专门的T细胞亚群-CD8+CD122+CD49d高调节性T细胞-是最早进入的 脑缺血，甚至先于CD4+Tregs和Bregs的渗透。CD8+的主要功能 Tregs是调节其他免疫细胞，特别是效应性T淋巴细胞的活性，并维持 免疫动态平衡。我们发现选择性地耗尽循环中的CD8+Tregs会加重脑损伤 和卒中后3天和7天的功能结果，这种情况可以通过重建 CD8+树突状细胞。这些令人兴奋的结果表明，CD8+Tregs是脑缺血的天然防御者 受伤。进一步的初步研究发现：1)CD8+Treg的早期保护依赖于它们的渗透 由于CD8+Tregs缺乏“脑靶向信号”，CXCR3不会渗透到缺血的大脑中。 在CD8+Treg耗尽的小鼠中，它们可以减少脑缺血，并失去减少脑梗塞的能力。2) 浸润性CD8+Tregs在脑内渗透和转录时进行基因组重编程 一组具有消炎和/或神经恢复功能的基因上调， 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(ETGF)。3)卒中后CD8+Tregs过继转移明显减少脑梗塞，增强 白质完整性，并改善神经功能，直到tMCAO后14d。4)收养转让 ETGF缺乏的CD8+Treg不能预防tMCAO。目前的提案将进一步探讨其影响 CD8+Treg在缺血性卒中中的应用及CD8+Treg过继转移作为免疫治疗的研究 治疗中风。有待检验的新中心假设是，CD8+Tregs的大脑渗透促进了 卒中后通过LIF/LIFR/ETGF介导的神经保护的长期神经恢复，解决 神经炎症和神经恢复机制。提出了三个具体目标。目标1.建立 卒中后CD8+Tregs过继移植治疗急性脑缺血的临床研究 脑梗塞。目的2.验证中风后CD8+Tregs过继移植促进长期治疗的假说 缺血性卒中后的神经功能恢复和神经功能恢复。目标3.检验假设 LiF/LIFR介导的ETGF释放对CD8+Treg提供的神经保护和 神经修复。这项研究将首次严格研究CD8+Tregs在脑缺血中的作用 受伤。这一结果将提高我们对中风免疫调节的理解，并为CD8+Treg的研究提供线索 转移作为一种潜在的治疗策略。