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疾病的病理生理学有关 因此，免疫调节已成为一种有前景的中风调节疗法。 淋巴细胞，包括 CD4+CD25+ 调节性 T 细胞 (CD4+Tregs) 和 IL-10+ 调节性 B 细胞 (Bregs) 我们最近发现了另一种在受伤大脑中调节免疫反应的方法。 专门的 T 细胞亚群——CD8+CD122+CD49d 高调节性 T 细胞——是最先进入的细胞之一。 缺血性大脑，甚至在 CD4+ Tregs 和 Bregs 浸润之前 CD8+ 的主要功能。 Tregs的作用是调节其他免疫细胞，特别是效应T淋巴细胞的活性，并维持 我们发现循环 CD8+ Tregs 的选择性耗竭会加重脑损伤。 以及中风​​后 3 天和 7 天的功能结果，这可以通过重构 CD8+ Tregs 这些令人兴奋的结果表明 CD8+ Tregs 是对抗缺血性大脑的天然防御者。 进一步的初步研究发现：1）CD8+ Treg 提供的早期保护依赖于它们的渗透。 进入缺血大脑，因为缺乏“大脑靶向信号”CXCR3 的 CD8+ Tregs 不会渗透到缺血大脑中 CD8+ Treg 缺失的小鼠大脑缺血并失去减少脑梗塞的能力 2)。 浸润的 CD8+ Tregs 在大脑浸润和转录后经历基因组重编程 上调一组具有消炎和/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 (ETGF) 3) 中风后 CD8+ Tregs 的过继转移显着减少脑梗塞，增强 白质完整性，并在 tMCAO 后 14 天内改善神经功能 4) 过继转移。 ETGF 缺陷的 CD8+ Treg 无法预防 tMCAO。目前的提案将进一步探讨其影响。 CD8+ Tregs 在缺血性中风中的作用，并开发 CD8+ Tregs 过继转移作为免疫治疗疗法 待测试的新的中心假设是 CD8+ Tregs 的大脑浸润会促进中风。 通过 LIF/LIFR/ETGF 介导的神经保护作用实现中风后长期神经功能恢复，解决 提出了三个具体目标： 目标 1. 建立。 中风后 CD8+ Tregs 过继转移作为针对急性缺血性脑的临床相关治疗 目标 2. 检验中风后 CD8+ Tregs 过继转移促进长期的假设。 缺血性中风后的神经恢复和神经恢复 目标 3. 检验以下假设： LIF/LIFR 介导的 ETGF 释放对于 CD8+ Treg 提供的神经保护和 这项研究将是第一个严格研究 CD8+ Tregs 在缺血性大脑中的作用的研究。 这些结果将提高我们对中风免疫调节的理解，并为 CD8+ Treg 提供线索。 转移作为一种潜在的治疗策略。