Myelin-reactivity of a novel population of T cells infiltrating the normal aging monkey brain

浸润正常衰老猴脑的新型 T 细胞群的髓磷脂反应性

• 批准号: 10222549
• 负责人: Katelyn Trecartin
• 金额: $ 5.1万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2023-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222549
• 关键词: Adaptive Immune System; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Antigen Presentation; Archives; Autoimmune Diseases; Autologous; Automobile Driving; Axon; Belief; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; CD3 Antigens; CD8B1 gene; Cell Culture Techniques; Cerebral cortex; Cervical lymph node group; Chronic; Cognitive; Cognitive aging; Data; Demyelinations; Development; Disease; Drug usage; Encephalitis; Endothelial Cells; Exhibits; Extravasation; FOXP3 gene; Flow Cytometry; Fresh Tissue; Future; Gene Expression; Gene Expression Profile; Goals; Human; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Impairment; Infiltration; Inflammation; Inflammatory; Integrins; Interferon-beta; Investigation; Investigational Therapies; Label; Lead; Learning; Ligands; Longevity; Macaca mulatta; Maintenance; Memory; Microglia; Modeling; Monkeys; Multiple Sclerosis; Myelin; Myelin Basic Proteins; Myelin Sheath; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Peripheral; Phagocyte Bactericidal Dysfunction; Phagocytes; Phenotype; Physicians; Play; Population; Preparation; Regulatory T-Lymphocyte; Reporting; Role; Route; Scientist; Selectins; Series; Severities; Slice; Stains; T cell therapy; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tissue Sample; Tissues; Training; Tumor-infiltrating immune cells; Work; age related; age related neuroinflammation; aged; aging brain; anti-IgG; autoreactive T cell; autoreactivity; behavior test; brain parenchyma; brain tissue; cell injury; cognitive testing; cytotoxic; executive function; experimental study; functional disability; gray matter; insight; lymphatic drainage; neuroinflammation; neuron loss; normal aging; novel; novel therapeutics; preservation; prevent; recruit; reflectance confocal microscopy; sex; skills; trafficking; transcriptome sequencing; white matter; white matter damage

ABSTRACT Normal human aging is characterized by cognitive impairments in executive function, learning and memory even in the absence of the neurodegeneration of Alzheimer's Disease (AD). While such cognitive aging was long believed to be due to neuronal loss, stereologic investigations of humans free of AD have shown that neurons are not lost, but instead myelin pathology increases and white matter is lost. The rhesus monkey is a valuable model of normal aging as they are spared the overt neurodegeneration of AD but still exhibit cognitive decline similar to humans. Examining the brains of cognitively assessed monkeys, we have found that the myelin shows splitting and ballooning of sheaths that likely impairs axonal conduction velocity and may lead to axon loss and reduced white matter volume. Importantly, myelin pathology correlates with age-related cognitive impairment in the monkey. While the mechanisms underlying this white matter pathology are still unknown, our lab has found that activation and phagocytic dysfunction of microglia increases in the white matter with age and correlates with cognitive decline. In pursuing this problem, I recently discovered that age-related increases in brain inflammation are accompanied by infiltration of peripheral T cells into the white matter in the same loci where myelin pathology is prevalent. These results challenge the concept that the brain is 'immune privileged' and instead might be vulnerable to infiltration of peripheral T cells leading to auto-attack and secondary inflammatory damage. Moreover, T cells do not infiltrate the aging gray matter, suggesting that infiltration is tissue specific and may play a role in age-related white matter pathology. The goal of this project is to determine why T cells infiltrate the aging brain and what their function is within in the white matter in parenchyma. I will perform a series of experiments on brain tissue from cognitively tested rhesus monkeys to test the hypothesis that age-related neuroinflammation leads to parenchymal infiltration of T cells where they are myelin-reactive and contribute to age-related myelin pathology. In Aim 1, I will explore how T cells are trafficked into the brain, what T cell subtypes are present and how T cells are related to myelin pathology. This will be accomplished using immunohistochemistry to label T cells and spectral confocal reflectance (SCoRe) microscopy to quantify myelin. In Aim 2, I will investigate the function of infiltrating T cells by analyzing their gene expression patterns using RNA sequencing and assessing their myelin reactivity and involvement in myelin sheath damage using organotypic slice cultures. To experimentally modulate T cell activity, the cultures will be treated with two therapeutics that target T cells and reduce damage to myelin in multiple sclerosis. In addition to characterizing brain parenchymal T cells with age, I will discover whether infiltrating T cells are myelin reactive and if they contribute to the white matter pathology and the severity of cognitive impairment. These data should identify targets for future experimental and therapeutic interventions to slow or prevent brain aging.

抽象的 正常的人类衰老的特征是执行功能，学习和记忆的认知障碍甚至 在没有阿尔茨海默氏病（AD）神经退行性的情况下。虽然这种认知衰老很长 认为是由于神经元丧失造成的，对人类没有AD的立体学研究表明神经元 不会丢失，而是髓磷脂病理学增加，白质丢失。恒河猴是有价值的 正常衰老的模型免于AD的明显神经变性，但仍表现出认知能力下降 类似于人类。检查认知评估的猴子的大脑，我们发现髓磷脂显示 可能会损害轴突传导速度的鞘的分裂和气球，并可能导致轴突丢失和 减少了白质体积。重要的是，髓磷脂病理与年龄相关的认知障碍相关 猴子。虽然这种白质病理学基础的机制仍然未知，但我们的实验室发现 小胶质细胞的激活和吞噬性功能障碍随着年龄的增长而增加，并与 认知能力下降。在追求这个问题时，我最近发现与年龄相关的脑部炎症增加 伴随着外周T细胞在同一基因座中的白质中浸润 很普遍。这些结果挑战了大脑“免疫特权”的概念，而是可能是 容易受到周围T细胞的渗透，从而导致自动攻击和继发性炎症损伤。 此外，T细胞不会浸润衰老的灰质，表明浸润是组织特异性的，可能 在与年龄有关的白质病理学中发挥作用。该项目的目的是确定为什么T细胞渗入 大脑衰老及其功能在实质中的白质中的功能。我将执行一系列 从认知测试的恒河猴对脑组织进行的实验，以检验与年龄相关的假设 神经炎症会导致T细胞实质浸润，在这些细胞中，它们具有髓磷脂反应性，并有助于 与年龄有关的髓磷脂病理学。在AIM 1中，我将探讨如何将T细胞流入大脑，哪种T细胞亚型 存在以及T细胞与髓磷脂病理学的关系。这将使用 对标记T细胞和光谱共聚焦反射率（得分）显微镜的免疫组织化学来量化髓磷脂。 在AIM 2中，我将通过使用使用其基因表达模式来研究浸润T细胞的功能 使用RNA测序和评估其髓鞘的反应性，并使用使用 器官切片培养物。为了实验调节T细胞活性，将用两个 靶向T细胞并减少多发性硬化症中髓磷脂损伤的疗法。除了表征 脑实质T细胞随着年龄的增长，我会发现浸润的T细胞是否是髓磷脂反应性的 有助于白质病理学和认知障碍的严重程度。这些数据应确定 未来的实验和治疗干预措施的目标，以减缓或防止大脑衰老。