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

• 批准号: 10391533
• 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
• 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/10391533
• 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

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.

摘要 恶性疟原虫感染最严重的临床并发症是脑型疟疾（CM）， 尽管治疗，发病率仍很高。疟疾的传播正变得越来越严重， 恶性疟原虫对用于治疗这种疾病的传统药物产生了抗药性。基于上述原因， 了解CM的病因对于治疗这一高度重要的全球性问题至关重要。最近，更严格的 已经对CM患者进行了大规模MRI研究。正如先前的假设， 血脑屏障（BBB）、广泛水肿和脑肿胀与致命的人类CM相关。鉴于 以上在人CM中的观察结果，需要解释BBB破坏和血管通透性的机制。 定义了伯氏疟原虫ANKA（PbA）感染小鼠是一种已建立的人CM模型。 与PbA感染相关的相当多的CNS病理学由急性CD 8 T细胞应答驱动， 诱导BBB紧密连接蛋白和CNS血管通透性的破坏。使用我们的新型MHC I类 条件性基因敲除小鼠，我们已经确定巨噬细胞和树突状细胞引发非等效 CD 8 T细胞对PbA感染的应答当两种抗原呈递细胞都引发CD 8 T细胞时， 当CD 8 T细胞浸润脑组织时，只有树突状细胞引起的CD 8 T细胞才能诱导致命的血脑屏障 破坏我们的中心假设是，特定的APC亚群，即巨噬细胞，小胶质细胞， 树突状细胞有助于产生针对PbA的不同脑浸润性CD 8 T细胞应答 感染这些不同的CD 8 T细胞应答具有不同的诱导致死性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CD 11 c + APC引起的脑浸润性CD 8 T细胞库 急性PbA感染。 具体目标#2 -鉴定CD 8 T细胞介导的BBB破坏所需的CD 11 c + APC。 具体目标#3 -确定由不同抗原引发的CD 8 T细胞群的能力 呈现细胞类型以在PbA感染的效应期期间造成BBB破坏。 这项工作是创新的，因为它利用了我们独特的转基因小鼠模型， 方法学，以及马约诊所研究项目的新核心设施。我们的目标是定义 在实验性人CM中，炎症对BBB破坏的作用机制是通过 使用领先的实验模型获得的知识。除了所采用的创新方法外， 抗原呈递细胞引起不同的CD 8 T细胞应答的概念是一个非常新颖的发现， 需要进一步研究治疗靶向机制。这一点尤其重要，如果 体内CD 8 T细胞引发的一种形式是引发致命的神经疾病。