T Cell Immunity in Giant Cell Arteritis

巨细胞动脉炎中的 T 细胞免疫

基本信息

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
项目类别：
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

项目摘要

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.

项目概要巨细胞动脉炎（GCA）是一种威胁视力的血管炎，由于血管闭塞而导致眼部缺血。供应视神经、视网膜、虹膜或其他眼眶结构的关键动脉。 GCA 视力丧失的主要原因是动脉炎性前部缺血性视神经病变 (AION) 或视网膜中央动脉闭塞，如果该疾病得到诊断并有进展到第二只眼的风险，那么失明是可以预防的。 GCA 患者接受高反应性 CD4 T 细胞治疗，这些细胞侵入动脉壁层。它们与巨噬细胞一起诱导管腔闭塞性内膜增生，从而导致 CD4 T 的缺陷。细胞高反应性尚不清楚，当前的应用程序将检验 CD4 T 细胞的假设。 GCA 患者未能激活免疫保护性程序性细胞死亡蛋白 1 (PD-1) 在结合其配体程序性死亡配体 1 (PD-L1) 后，PD-1 受体会传递 STOP。该提案建立在初步研究表明低水平的基础上。来自 GCA 的树突状细胞 (DC) 和内皮细胞 (EC) 上 PD-L1 免疫抑制配体的表达此外，在携带人类动脉和 GCA 的嵌合小鼠中阻断 PD-1 免疫检查点。 CD4 T 细胞导致血管炎显着恶化，诱导内皮-间质转化并加剧了内膜层的生长。本提案中设计的实验依赖于一系列的支持。资源，特别是针对大量 GCA 患者、受 GCA 影响的颞动脉生物库以及嵌合体系统，在移植到免疫缺陷小鼠体内的人类动脉中诱导血管炎。具体目标 1 在机制水平上检查 PD-L1low 树突状细胞如何影响持续时间、实验的目的是提高血管炎性免疫反应的幅度和质量。了解 PD-L1 表达不足如何调节 T 细胞激活、扩增、组织侵袭、具体目标 2 研究外膜上 PD-L1 的表达情况。微血管内皮细胞（MVEC）保护血管壁免受免疫攻击，保护血管在体外和体内，我们将定义 MVEC 衍生的负信号如何调节行为。 PD-1+ CD4 T 细胞和效应器功能以及内皮 PD-L1 缺陷如何促进血管生成性 T 具体目标 3 将确定导致 GCA DC 上 PD-L1 表达不足的机制，其中通过筛选 GCA 和对照 DC 的反应性来修复有缺陷的免疫检查点。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 PD-L1 表达的关键调节因子。患者来源的 DC 对 IFN-γ 不敏感，并且无法上调。我们将探讨经典骨形态发生蛋白 (BMP4) 信号传导的功能。 pSMAD1/5-IRF1 信号轴并使用 ATAC 通过表观遗传学研究补充这些实验测序以确定差异染色质可及性和调节转录因子网络的区域。