CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

CD8 T 细胞介导的血脑屏障紧密连接破坏

基本信息

批准号：
10199061
负责人：
Aaron J Johnson
金额：
$ 41.21万
依托单位：
MAYO CLINIC ROCHESTER
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：
2017-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10199061
关键词：
Ablation Acute Adoptive Transfer Antigen-Presenting Cells Biological Markers Blood - brain barrier anatomy Brain Brain Edema C57BL/6 Mouse CD11c Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cells Cerebral Malaria Clinic Clinical Clinical Research Complication Core Facility Cytometry Data Dendritic Cells Deposition Drug usage Edema Employment Etiology Experimental Models Fibrinogen Generations Goals Human ITGAX gene Image Immune Infection Inflammation Inflammatory Investigation Knockout Mice Knowledge Location Lymphocyte Subset MHC Class I Genes Magnetic Resonance Imaging Malaria Mediating Methodology Microglia Modeling Morbidity - disease rate Mus Nature Parabiosis Pathology Patients Pharmaceutical Preparations Phase Plasmodium berghei Plasmodium falciparum Population Proteins Protocols documentation Publishing Reporting Research Resistance Resistance development Role Severity of illness System T cell response Testing Tight Junctions Tissues Transgenic Mice Transgenic Organisms Vascular Endothelial Growth Factors Vascular Permeabilities Work blood-brain barrier disruption brain endothelial cell cell type conditional knockout cytotoxicity experimental study human disease human model in vivo innovation macrophage magnetic resonance imaging biomarker mouse model nervous system disorder neuropathology novel perforin programs response therapeutic target

项目摘要

ABSTRACT The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM) which has high morbidity despite treatment. The spread of malaria is becoming increasingly more serious as Plasmodium falciparum develops resistance to traditional drugs used to treat the condition. For the above reasons, understanding the etiology of CM is critical to treat this highly significant global issue. Recently, more rigorous large scale MRI studies have been conducted on CM patients. As previously hypothesized, disruption of the blood-brain barrier (BBB), extensive edema, and brain swelling are associated with fatal human CM. Given the above observations in human CM, the mechanism of BBB disruption and vascular permeability needs to be defined. Plasmodium berghei ANKA (PbA) infection of mice is an established model of human CM. Considerable CNS pathology associated with PbA infection is driven by an acute CD8 T cell response which induces disruption of BBB tight junction proteins and CNS vascular permeability. Using our novel MHC class I conditional knockout mice, we have determined that macrophages and dendritic cells prime non-equivalent CD8 T cell responses in response to PbA infection. While both antigen presenting cells prime CD8 T cell response that infiltrate the brain, only CD8 T cells raised by dendritic cells induce lethal blood-brain barrier disruption. Our central hypothesis is that specific APC subsets, namely macrophages, microglia, and dendritic cells, contribute to the generation distinct brain infiltrating CD8 T cell responses against PbA infection. These distinct CD8 T cell responses have differential ability to induce fatal BBB disruption. We plan to test this central hypothesis through execution of the following specific aims: Specific Aim #1 – Define the brain infiltrating CD8 T cell repertoire raised by LysM+ and CD11c+ APCs during acute PbA infection. Specific Aim #2 – Identify the CD11c+ APC required for CD8 T cell mediated BBB disruption. Specific Aim #3 – Determine the capacity of CD8 T cell populations primed by distinct antigen presenting cell types to inflict BBB disruption during the effector phase of PbA infection. The proposed work is innovative because it capitalizes on our unique transgenic mouse models, novel imaging methodology, and new core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of inflammation to BBB disruption in experimental human CM through knowledge gained using a leading experimental model. Beyond the innovative methodology employed, the concept that antigen presenting cells raise differential CD8 T cell responses is a highly novel finding which warrants further investigation to a mechanism which is therapeutically targetable. This is especially important if one form of CD8 T cell priming in vivo is initiating lethal neurological disease.

抽象的恶性疟原虫感染最严重的临床并发症是脑型疟疾（CM），尽管接受了治疗，疟疾的传播却变得越来越严重。由于上述原因，恶性疟原虫对用于治疗这种疾病的传统药物产生了耐药性。了解 CM 的病因学对于治疗这一高度重要的全球性问题至关重要。正如之前所研究的那样，对 CM 患者进行了大规模的 MRI 研究。血脑屏障 (BBB)、广泛水肿和脑肿胀与致命的人类 CM 相关。根据上述在人类 CM 中的观察结果，需要了解 BBB 破坏和血管通透性的机制伯氏疟原虫 ANKA (PbA) 感染小鼠是已建立的人类 CM 模型。与 PbA 感染相关的相当多的中枢神经系统病理是由急性 CD8 T 细胞反应驱动的，使用我们的新型 MHC I 类诱导 BBB 紧密连接蛋白和 CNS 血管通透性破坏。条件敲除小鼠，我们确定巨噬细胞和树突状细胞不等价 CD8 T 细胞对 PbA 感染作出反应，同时两种抗原呈递细胞都启动 CD8 T 细胞。渗透大脑的反应，只有树突状细胞产生的 CD8 T 细胞才会诱导致命的血脑屏障我们的中心假设是特定的 APC 亚群，即巨噬细胞、小胶质细胞和树突状细胞，有助于产生针对 PbA 的独特脑浸润 CD8 T 细胞反应这些不同的 CD8 T 细胞反应具有不同的诱导致命 BBB 破坏的能力。我们计划通过执行以下具体目标来检验这一中心假设：具体目标 #1 – 定义由 LysM+ 和 CD11c+ APC 产生的大脑浸润 CD8 T 细胞库急性 PbA 感染期间。具体目标#2 – 识别 CD8 T 细胞介导的 BBB 破坏所需的 CD11c+ APC。具体目标 #3 – 确定由不同抗原引发的 CD8 T 细胞群的能力在 PbA 感染的效应器阶段呈现细胞类型以造成 BBB 破坏。拟议的工作具有创新性，因为它利用了我们独特的转基因小鼠模型、新颖的成像技术我们的目标是定义梅奥诊所研究项目的方法论和新的核心设施。从机制上讲，炎症对实验性人类 CM 中 BBB 破坏的贡献除了使用领先的实验模型之外，还获得了知识。抗原呈递细胞引发差异性 CD8 T 细胞反应的概念是一个非常新颖的发现，需要进一步研究可治疗的靶向机制，如果这一点尤其重要。 CD8 T 细胞体内启动的一种形式是引发致命的神经系统疾病。