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

基本信息

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
项目类别：
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

项目摘要

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。