T Cell Immunity in Giant Cell Arteritis

巨细胞动脉炎中的 T 细胞免疫

• 批准号: 10457645
• 负责人: Cornelia M. Weyand
• 金额: $ 35.48万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457645
• 关键词: Affect; Anterior Ischemic Optic Neuropathy; Antigen-Presenting Cells; Arteries; Arteritis; Autoimmunity; Automobile Driving; Behavior; Binding; Biological Assay; Blindness; Blood Vessels; Bone Morphogenetic Proteins; Brain; CD4 Positive T Lymphocytes; Cell Mobility; Cell Shape; Central Retinal Artery Occlusion; Chimera organism; Chromatin; Clinical; Complement; Critical Pathways; Data; Defect; Dendritic Cells; Diagnosis; Disease; Down-Regulation; Elements; Emergency Situation; Endothelial Cells; Endothelium; Enhancers; Epigenetic Process; Eye; Fright; Giant Cells; Goals; Granulomatous; Human; Hyperplasia; IRF1 gene; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; In Vitro; Infiltration; Inflammation; Inflammatory; Interferon Type II; Invaded; Iris; Ischemia; Lesion; Ligands; Malignant Neoplasms; Maps; Mesenchymal; Molecular; Mus; Ocular orbit; Ophthalmology; Optic Nerve; Pathogenicity; Patients; Physiological; Production; Regulation; Reporter Genes; Resources; Retina; Series; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stroke; Structure; System; T-Cell Activation; T-Lymphocyte; Temporal Arteries; Temporal Arteritis; Tissues; Toxic effect; Transcriptional Regulation; Tumor Immunity; Vasculitis; Vision; Visual; XCL1 gene; autoimmune vasculitis; biobank; body system; cell motility; checkpoint inhibition; checkpoint receptors; cohort; cytokine; design; effector T cell; experimental study; high risk; hypoperfusion; immune activation; immune checkpoint; immunoregulation; in vivo; inhibitor/antagonist; macrophage; prevent; programmed cell death ligand 1; programmed cell death protein 1; promoter; receptor; recruit; repaired; response; restoration; screening; transcription factor; tumor; vascular inflammation

Project Summary Giant cell arteritis (GCA) is a vision-threatening vasculitis that causes ocular ischemia due to occlusion of critical arteries supplying the optic nerve, the retina, the iris, or other orbital structures. The typical presentation of vision loss in GCA is arteritic anterior ischemic optic neuropathy (AION) or central retinal artery occlusion, with a high risk for progression to the second eye. Blindness is preventable if the disease is diagnosed and treated promptly. GCA patients have hyperreactive CD4 T cells that invade into the wall layers of arteries where together with macrophages they induce lumen-occlusive intimal hyperplasia. The defect driving CD4 T cell hyperreactivity is not understood. The current application will examine the hypothesis that CD4 T cells from GCA patients fail to activate the immuno-protective Programmed cell death protein 1 (PD-1) checkpoint. Upon binding its ligand Programmed death-ligand 1 (PD-L1), the PD-1 receptor transmits a STOP signal to inhibit T cell effector functions. The proposal builds on preliminary studies demonstrating low expression of the PD-L1 immuno-inhibitory ligand on dendritic cells (DC) and endothelial cells (EC) from GCA patients. Also, blockade of the PD-1 immune checkpoint in chimeric mice carrying human arteries and GCA CD4 T cells results in marked exacerbation of vasculitis, induces endothelial-mesenchymal transition and aggravates intimal layer outgrowth. Experiments designed in this proposal rely on a series of enabling resources, specifically on a large cohort of GCA patients, a biobank of GCA-affected temporal arteries and a chimera system in which vasculitis is induced in human arteries engrafted into immune-deficient mice. Specific Aim 1 examines on a mechanistic level how PD-L1low dendritic cells affect the duration, the amplitude and the quality of vasculitogenic immune responses. Experiments have been designed to understand how insufficient expression of PD-L1 modulates T cell activation, expansion, tissue invasion, survival and cytokine production. Specific Aim 2 investigates how PD-L1 expression on adventitial microvascular endothelial cells (MVEC) shields the vessel wall from immune attack and protects vascular barrier function. In vitro and in vivo, we will define how MVEC-derived negative signals modulate the behavior and effector functions of PD-1+ CD4 T cells and how endothelial PD-L1 deficiency promotes vasculitogenic T cells. Specific Aim 3 will identify mechanisms leading to insufficient PD-L1 expression on GCA DC, with the goal to repair the defective immune checkpoint. By screening the responsiveness of GCA and control DC to stimuli and signaling pathway inhibitors, we have discovered the IFN-γ-BMP4-pSMAD1/5-IRF1 module as a critical regulator of PD-L1 expression. Patient-derived DC display IFN-γinsensitivity and fail to upregulate canonical bone morphogenetic protein (BMP4) signaling. We will probe the functionality of the BMP4- pSMAD1/5-IRF1 signaling axis and complement these experiments with epigenetic studies using ATAC sequencing to define regions of differential chromatin accessibility and regulatory transcription factor networks.

项目摘要 巨细胞动脉炎（GCA）是一种威胁视力的血管炎，由于阻塞 提供视神经，视网膜，虹膜或其他轨道结构的关键动脉。典型的演示 GCA的视力丧失是动脉前缺血性视神经病（AION）或中央永久性动脉闭塞， 有高风险向第二眼进展。如果诊断出该疾病并可以预防失明 迅速治疗。 GCA患者具有侵入动脉壁层的高回应性CD4 T细胞 它们与巨噬细胞一起诱导了流明的内膜增生。驾驶CD4 T的缺陷 细胞过度反应性尚不清楚。当前的应用将检查CD4 T细胞的假设 来自GCA患者未能激活免疫保护程序细胞死亡蛋白1（PD-1） 检查点。在结合其配体编程的死亡配体1（PD-L1）后，PD-1受体会传输停止 信号以抑制T细胞效应子的功能。该提案以初步研究为基础，表明低 PD-L1免疫抑制性配体在树突状细胞（DC）和内皮细胞（EC）上的表达 患者。另外，携带人动脉和GCA的嵌合小鼠中PD-1免疫骨骼桶 CD4 T细胞会导致血管炎的显着加重，诱导内皮间质转变和 加重内膜层的生长。本提案中设计的实验取决于一系列支持 资源，特别是大量GCA患者，由GCA影响的临时动脉和A 嵌合体系统在涉及免疫缺陷小鼠的人类动脉中诱导血管炎。 在机械水平上的特定目标1检查PD-L1LOW树突状细胞如何影响持续时间， 放大器和血管生成免疫反应的质量。实验已设计为 了解PD-L1表达不足如何调节T细胞激活，扩展，组织侵袭， 生存和细胞因子产生。特定目标2调查了PD-L1在冒险上的表达方式 微血管内皮细胞（MVEC）保护血管壁免疫攻击并保护血管 屏障功能。在体外和体内，我们将定义MVEC衍生的负信号如何调节行为 PD-1+ CD4 T细胞的效应函数以及内皮PD-L1缺乏症如何促进血管生成T 细胞。具体目标3将确定导致GCA DC上PD-L1表达不足的机制，并且 维修有缺陷的免疫切口点的目标。通过筛选GCA和控制DC的响应能力 刺激和信号通路抑制剂，我们发现了IFN-γ-BMP4-PSMAD1/5-IRF1模块作为A PD-L1表达的关键调节剂。患者来源的直流显示IFN-γ敏感性，无法更新 规范骨形态发生蛋白（BMP4）信号传导。我们将探测BMP4-的功能 PSMAD1/5-IRF1信号传导轴并完成了使用ATAC进行表观遗传学研究的实验 测序以定义差异染色质可及性和调节转录因子网络的区域。