T Cell Immunity in Giant Cell Arteritis

巨细胞动脉炎中的 T 细胞免疫

• 批准号: 9523030
• 负责人: Cornelia M. Weyand
• 金额: $ 39.25万
• 依托单位: STANFORD UNIVERSITY
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9523030
• 关键词: Affect; Anterior Ischemic Optic Neuropathy; Antigen-Presenting Cells; Apoptosis; 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; Effector Cell; Elements; Emergency Situation; Endothelial Cells; 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; PDCD1LG1 gene; Pathogenicity; Patients; Physiological; Production; Proteins; Regulation; Reporter Genes; Resources; Retina; SLEB2 gene; 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; experimental study; high risk; hypoperfusion; immune activation; immune checkpoint; immunoregulation; in vivo; inhibitor/antagonist; macrophage; prevent; 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，由于眼部闭塞导致眼部缺血。 供应视神经、视网膜、虹膜或其他眼眶结构的关键动脉。典型演示文稿 在GCA中，视力丧失的原因是动脉炎性前部缺血性视神经病变(AION)或视网膜中央动脉阻塞， 有很高的发展到第二只眼睛的风险。如果这种疾病被诊断出来，失明是可以预防的 得到了及时治疗。GCA患者有高反应性的CD4T细胞侵入动脉壁层 它们与巨噬细胞一起诱导管腔闭塞的内膜增生。驱动CD4T的缺陷 细胞的高反应性目前还不清楚。目前的应用将检验一种假设，即CD4T细胞 GCA患者未能激活免疫保护性程序性细胞死亡蛋白1(PD-1) 检查站。一旦与其配体程序性死亡配体1(PD-L1)结合，PD-1受体就会停止传递 抑制T细胞效应器功能的信号。该提案建立在初步研究表明 PD-L1免疫抑制配体在GCA树突状细胞和内皮细胞上的表达 病人。此外，阻断携带人动脉和GCA的嵌合小鼠的PD-1免疫检查点 CD4T细胞导致血管炎显著加重，诱导内皮细胞-间充质转化和 加重内膜层外延生长。本方案中设计的实验依赖于一系列使能 资源，特别是关于大量GCA患者的资源，受GCA影响的颞动脉生物库和 在植入免疫缺陷小鼠的人动脉中诱发血管炎的嵌合体系统。 特殊目的1在机制水平上检查PD-L1低树突状细胞如何影响持续时间， 血管生成免疫反应的幅度和质量。实验的目的是为了 了解PD-L1表达不足如何调节T细胞的激活、扩增、组织侵袭、 生存和细胞因子的产生。特异性目标2研究PD-L1在外膜上的表达 微血管内皮细胞(MVEC)保护血管壁免受免疫攻击 屏障功能。在体外和体内，我们将定义MVEC衍生的负面信号如何调节行为 和PD-1+CD4T细胞的效应功能以及内皮PD-L1缺陷如何促进血管生成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， 目标是修复有缺陷的免疫检查点。通过筛选GCA的反应性和控制DC对 刺激和信号通路抑制剂，我们发现干扰素-γ-骨形态发生蛋白4-pSMAD1/5-irf1模块作为一种 PD-L1表达的关键调控因子。患者来源的DC对干扰素-γ不敏感，未能上调 规范骨形态发生蛋白(BMP4)信号转导。我们将探索BMP4的功能- PSMAD1/5-IRF1信号轴，并用ATAC进行表观遗传学研究来补充这些实验 测序以确定不同染色质可及性和调控转录因子网络的区域。