Ocular Disease in Giant Cell Arteritis

巨细胞动脉炎眼部疾病

基本信息

批准号：
7464879
负责人：
Cornelia M. Weyand
金额：
$ 30.95万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7464879
关键词：
3-Dimensional Acute Affect Alleles Anterior Ischemic Optic Neuropathy Antibodies Antigen-Presenting Cells Arteries Bacteria Binding Biomedical Engineering Blindness Blood Vessels CD28 gene CD4 Positive T Lymphocytes CTLA4-Ig Candidate Disease Gene Cell Communication Cell Differentiation process Cell physiology Cell surface Cells Chimera organism Chimeric Proteins Condition Data Defect Dendritic Cells Dendritic cell activation Development Diagnosis Disease Disruption Effector Cell Emergency Situation Epigenetic Process Event Eye Failure Frequencies Gene Expression Genes Genetic Transcription Granulomatous Histone Deacetylase Inhibitor Human Hyperplasia Immune Immune response Immunosuppressive Agents Implant Indigenous Individual Infection Infiltration Inflammation Inflammatory Instruction Invaded Invasive Ischemia Ischemic Optic Neuropathy Lead Lesion Ligands Link Localized Lymphocyte Measures Mediating Mesentery Messenger RNA Modeling Molds Molecular Molecular Profiling Obstruction Outcome Pathogenesis Pathway interactions Patients Pattern Physiological Positioning Attribute Predisposition Process Public Health Reaction Regulator Genes Repression Resistance Risk Role SCID Mice Sentinel Shapes Signal Transduction Small Interfering RNA Smooth Muscle Myocytes Stimulus Structure Structure of subclavian artery System T-Cell Activation T-Lymphocyte TLR3 gene TLR4 gene TLR5 gene Technology Temporal Arteritis Testing Therapeutic immunosuppression Tissue Engineering Tissues Toll-like receptors Transfusion Trichostatin A Tubular formation Tunica Adventitia Up-Regulation Vasculitis Virus Vision Visual Pathways Work anergy cell type chromatin remodeling clinical efficacy cohort concept design desire insight intracranial artery macrophage microbial novel novel therapeutics pathogen preclinical study preconditioning prevent programs promoter receptor reconstitution research study size tissue tropism vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Giant cell arteritis (GCA) is an immune-mediated vasculopathy with granulomatous inflammation of the arterial wall leading to lumenal obstruction and ischemia. The most common ophthalmic manifestation of GCA is anterior ischemic optic neuropathy causing acute visual loss in one or both eyes. Over the last decade, we have systematically deciphered the immunopathogenesis of GCA providing the conceptual framework for the current application. We hypothesize that dendritic cells (DC) indigenous to the artery initiate and sustain vasculitis by attracting, stimulating and instructing disease-relevant T cells. Whereas vascular DC in healthy arteries prevent immune stimulation, DC in GCA are hyperresponsive and compromise the artery's immunoprivilege. We have developed experimental systems which recapitulate the microenvironment in human arteries; human artery-SCID chimeras and bioengineered 3-D constructs resembling medium-sized human vessels. The current proposal presents three specific aims designed to mechanistically examine DC-T cell interactions leading to either desired T cell tolerance or pathological vascular inflammation. Aim 1 examines the hypothesis that CD28-CD86 interactions are critical in initiating vasculitis. Preliminary studies in GCA-resistant human arteries suggest selective repression of CD86 as a tolerance mechanism. Applying artery-SCID chimeras and tissue-engineered arteries, we will explore the role of CD86 by silencing this costimulatory ligand in DC or blocking with a soluble decoy receptor (CTLA4-Ig). Conversely, we will attempt to break tolerance by forced CD86 expression through epigenetic manipulation. Aim 2 examines the hypothesis that GCA development reflects defective coinhibitory signals, leading to unopposed T cell activation. Building on preliminary data showing overrepresentation of a low-expresser PD-L1 promoter allele and insufficient PD- L1 induction on DC from GCA patients, we will characterize mechanisms underlying defective PD-L1 signaling. We will continue preclinical studies aimed at developing a novel therapy for GCA by replenishing PD-L1 in the vasculitic lesions. Aim 3 will examine how vascular DC determine T cell effector functions mediating vasculitis. Specifically, we will search for molecules regulating T cell tissue-invasiveness, a prerequisite for the transmural progression of vasculitis. PUBLIC HEALTH RELEVANCE. GCA remains a sight-threatening disease and represents an ophthalmic emergency as blindness is preventable by prompt diagnosis and immunosuppressive therapy. This proposal examines how products from bacteria and viruses drive sentinel cells (so-called dendritic cells) in human arteries to become highly stimulatory and attract inflammatory lymphocytes. Receptor-ligand pairs utilized by inflammatory cells are examined with the hope that disruption of dendritic cell-lymphocyte interactions can be exploited for novel therapeutic strategies of this vision-threatening disease.

描述（由申请人提供）：巨细胞动脉炎（GCA）是一种免疫介导的血管病，伴有动脉壁肉芽肿性炎症，导致管腔阻塞和缺血。 GCA 最常见的眼科表现是前部缺血性视神经病变，导致一只或双眼急性视力丧失。在过去的十年中，我们系统地破译了 GCA 的免疫发病机制，为当前的应用提供了概念框架。我们假设动脉固有的树突状细胞 (DC) 通过吸引、刺激和指导与疾病相关的 T 细胞来引发和维持血管炎。健康动脉中的血管 DC 会阻止免疫刺激，而 GCA 中的 DC 反应过度，会损害动脉的免疫特权。我们开发了模拟人体动脉微环境的实验系统；人类动脉-SCID 嵌合体和生物工程 3D 结构，类似于中型人体血管。目前的提案提出了三个具体目标，旨在机械地检查 DC-T 细胞相互作用，从而导致所需的 T 细胞耐受或病理性血管炎症。目标 1 检查 CD28-CD86 相互作用对于引发血管炎至关重要的假设。对 GCA 耐药的人类动脉的初步研究表明选择性抑制 CD86 作为一种耐受机制。应用动脉-SCID嵌合体和组织工程动脉，我们将通过沉默DC中的这种共刺激配体或用可溶性诱饵受体（CTLA4-Ig）阻断来探索CD86的作用。相反，我们将尝试通过表观遗传操作强制 CD86 表达来打破耐受性。目标 2 检验了这样的假设：GCA 发育反映了有缺陷的共抑制信号，导致 T 细胞激活不受阻碍。基于初步数据显示低表达 PD-L1 启动子等位基因的过度表达以及 GCA 患者 DC 上的 PD-L1 诱导不足，我们将描述缺陷 PD-L1 信号传导的机制。我们将继续进行临床前研究，旨在通过补充血管炎病变中的 PD-L1 来开发治疗 GCA 的新疗法。目标 3 将检查血管 DC 如何确定介导血管炎的 T 细胞效应功能。具体来说，我们将寻找调节 T 细胞组织侵袭性的分子，这是血管炎透壁进展的先决条件。公共卫生相关性。 GCA 仍然是一种威胁视力的疾病，是一种眼科急症，因为失明是可以通过及时诊断和免疫抑制治疗来预防的。该提案研究了细菌和病毒的产物如何驱动人类动脉中的前哨细胞（所谓的树突细胞）变得高度刺激并吸引炎症淋巴细胞。对炎症细胞利用的受体-配体对进行了检查，希望能够利用树突状细胞-淋巴细胞相互作用的破坏来开发这种威胁视力的疾病的新治疗策略。