Chimeric antigen receptor T regulatory cells as therapy for Alzheimer's Disease

项目摘要/摘要： 阿尔茨海默病(AD)是一种进行性神经退行性疾病，是导致 60岁后记忆障碍和痴呆。额叶皮质中的神经元功能障碍和死亡 以及小胶质细胞介导的神经炎症和异常蛋白的形成 聚集物和纤维是AD的特征。散发性和家族性阿尔茨海默病具有生产过剩和/或 细胞外淀粉样β蛋白(Aβ)多肽清除减少和扭转tau蛋白的神经元内缠结 纤维。已知在AD中会发生神经炎症，当与Aβ斑块附近相关时， 神经退行性变。数据表明，炎性小胶质细胞，中枢神经驻留的巨噬细胞 系统，在神经退化和认知衰退中起作用。T调节细胞(Treg)是T细胞的一个子集 具有固有的抗炎和免疫调节特性。树在中枢神经系统的下面被发现 稳定的状态，并增加向中枢神经系统炎症区域的贩运。活跃度降低或减少 在AD患者中发现了大量的Tregs，Tregs的枯竭可以加速AD患者的认知障碍 小鼠AD模型。我们假设表达嵌合抗原受体(CARS)的Tregs具有特异性 淀粉样β蛋白(Aβ)在脑内具有治疗性免疫调节和局部疾病修饰活性 Aβ积聚和进行性神经变性的区域。这项提议的目的是测试创新的 Tregs被设计成表达针对Aβ的汽车的概念将展示免疫调节和 阿尔茨海默病小鼠模型的神经保护活性。我们将测试小鼠和人类的Tregs 当存在β时，AD模型中的活动。生成的数据将提供要移动的关键概念验证数据 这一新的治疗思想被提出

Project Summary/Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease that is one of the primary reasons for memory dysfunction and dementia after 60 years of age. Neuronal dysfunction and death in the frontal cortex and hippocampus, along with microglia-mediated neuroinflammation and formation of aberrant protein aggregates and fibrils are hallmarks of AD. Sporadic and familial forms of AD have an overproduction and/or decreased clearance of extracellular amyloid-beta (Aβ) peptides and intraneuronal tangles of twisted tau protein fibers. Neuroinflammation is known to occur in AD, and when associated near Aβ plaques there is a greater neurodegeneration. Data suggest that inflammatory microglia, the resident macrophages of the central nervous system, have a role in neurodegeneration and cognitive decline. T regulatory cells (Tregs) are a subset of T cells that have inherent anti-inflammatory and immunomodulatory properties. Tregs are found in the CNS under steady state conditions and increase trafficking to regions of CNS inflammation. Less active or decreased numbers of Tregs has been found in AD patients and depletion of Tregs can accelerate cognitive defects in murine AD models. We hypothesize that Tregs expressing chimeric antigen receptors (CARs) with specificity to amyloid-beta (Aβ) would have therapeutic immunomodulatory and localized disease-modifying activity at brain regions of Aβ accumulation and progressive neurodegeneration. The aim of this proposal is to test the innovative concept that Tregs engineered to express CARs against Aβ will demonstrate immunoregulatory and neuroprotective activities in mouse models of Alzheimer's disease. We will test murine and human Tregs for activity in AD models when Aβ is present. The data generated will provide key proof-of-concept data to move this novel therapeutic idea forward