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：
10609855
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/10609855
关键词：
Ablation Acute Adoptive Transfer Antigen-Presenting Cells Biological Markers Blood Vessels Brain Brain Edema C57BL/6 Mouse CD11c Antigens CD8-Positive T-Lymphocytes 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 Hemorrhage Human ITGAX gene Image Immune Immunity Infection Infiltration Inflammation Inflammatory Investigation Knockout Mice Knowledge Location Lymphocyte Subset MHC Class I Genes Macrophage Magnetic Resonance Imaging Malaria Mediating Methodology Microglia Modeling Morbidity - disease rate Mus Nature Parabiosis Pathology Patients Phase Plasmodium berghei Plasmodium falciparum Population Process Proteins Protocols documentation Publishing Reporting Research Resistance Resistance development Role Severity of illness System T cell response T cell therapy Testing Therapeutically Targetable 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 drug resistance development experimental study human disease human model in vivo innovation magnetic resonance imaging biomarker mouse model nervous system disorder neuropathology novel perforin programs response

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的最严重的临床并发症是脑疟疾（CM）高发病任务治疗。随着疟原虫，疟疾的传播变得越来越严重恶性发展对治疗疾病的传统药物的抵抗力。由于上述原因，了解CM的病因对于处理这个极为重大的全球问题至关重要。最近，更严格已经对CM患者进行了大规模MRI研究。如前所述，破坏了血脑屏障（BBB），广泛的水肿和脑肿胀与致命的人类商业有关。鉴于以上观察到人类商业的观察，BBB破坏和血管通透性的机制必须是定义。小鼠的Berghei Anka（PBA）感染是人类商业的既定模型。与PBA感染相关的相关CNS病理学是由急性CD8 T细胞反应驱动的诱导BBB紧密连接蛋白和CNS血管通透性的破坏。使用我们的小说MHC I类有条件的敲除小鼠，我们已经确定巨噬细胞和树突状细胞主要非等量响应PBA感染的CD8 T细胞反应。而两个抗原呈现细胞的主要CD8 T细胞浸润大脑的反应，只有树突状细胞饲养的CD8 T细胞诱导致命的血脑屏障破坏。我们的中心假设是特定的APC子集，即巨噬细胞，小胶质细胞和树突状细胞，有助于产生不同的脑浸润CD8 T细胞反应PBA 感染。这些独特的CD8 T细胞反应具有差异的诱导致命BBB破坏的能力。我们计划通过执行以下特定目的来检验这一中心假设：特定目标＃1 - 定义脑浸润CD8 T细胞库，由Lysm+和CD11C+ APC升高在急性PBA感染期间。特定目标＃2 - 确定CD8 T细胞介导的BBB破坏所需的CD11C+ APC。特定目的＃3 - 确定由不同抗原引发的CD8 T细胞群体的能力在PBA感染的效应阶段呈现细胞类型会导致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鼠标模型，新颖的成像我们在Mayo Clinic的研究计划可用的方法和新的核心设施。我们的目标是定义从机械上讲，炎症对实验性人CM中BBB破坏的贡献使用领先的实验模型获得的知识。超越了采用的创新方法，抗原呈现细胞产生差异CD8 T细胞反应的概念是一个高度新颖的发现保证进一步调查了一种在治疗上靶向的机制。如果这尤其重要 CD8 T细胞启动体内的一种形式是开始致命的神经系统疾病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.

TREM2 介导 MHCII 相关 CD4 T 细胞针对神经胶质瘤的反应。

DOI：
10.1093/neuonc/noad214
发表时间：
2023
期刊：
Neuro-oncology
影响因子：
15.9
作者：
Zheng,Jiaying;Wang,Lingxiao;Zhao,Shunyi;Zhang,Wenjing;Chang,Yuzhou;Bosco,DaleB;Huang,Tao;Dheer,Aastha;Gao,Shan;Xu,Shengze;Ayasoufi,Katayoun;Al-Kharboosh,Rawan;Qi,Fangfang;Xie,Manling;Johnson,AaronJ;Dong,Haidong;Quiñones-H
通讯作者：
Quiñones-H

Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease.

在保护和病理之间寻找平衡：穿孔素在人类疾病中的双重作用。

DOI：
10.3390/ijms18081608
发表时间：
2017
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Willenbring,RobinC;Johnson,AaronJ
通讯作者：
Johnson,AaronJ

Remyelination-Promoting DNA Aptamer Conjugate Myaptavin-3064 Binds to Adult Oligodendrocytes In Vitro.

DOI：
10.3390/ph13110403
发表时间：
2020-11-19
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
0
作者：
Fereidan-Esfahani M;Yue WY;Wilbanks B;Johnson AJ;Warrington AE;Howe CL;Rodriguez M;Maher LJ 3rd
通讯作者：
Maher LJ 3rd