Ocular Disease in Giant Cell Arteritis

巨细胞动脉炎眼部疾病

• 批准号: 8063921
• 负责人: Cornelia M. Weyand
• 金额: $ 30.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063921
• 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 physiology; Cell surface; Cells; Chimera organism; Chimeric Proteins; Data; Defect; Dendritic Cells; Dendritic cell activation; Development; Diagnosis; Disease; 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; Ischemia; Ischemic Optic Neuropathy; Lead; Lesion; Ligands; Link; Lymphocyte; Measures; Mediating; Mesenteric Arteries; Messenger RNA; Modeling; Molds; Molecular; Molecular Profiling; Obstruction; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Physiological; Positioning Attribute; Predisposition; Process; 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 anergy; T cell differentiation; T-Cell Activation; T-Lymphocyte; TLR3 gene; TLR4 gene; TLR5 gene; Technology; Temporal Arteries; Temporal Arteritis; Testing; Therapeutic immunosuppression; Tissue Engineering; Tissues; Toll-like receptors; Transfusion; Trichostatin A; Tubular formation; Tunica Adventitia; Up-Regulation; Vascular Diseases; Vasculitis; Virus; Vision; Visual Pathways; Work; anergy; cell type; chromatin remodeling; clinical efficacy; cohort; design; insight; intracranial artery; macrophage; microbial; novel; novel therapeutics; ophthalmic artery; pathogen; preclinical study; preconditioning; prevent; programs; promoter; public health relevance; receptor; reconstitution; research study; tissue tropism; vascular inflammation

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，具有动脉壁的肉芽肿性炎症，导致鼻腔阻塞和缺血。 GCA最常见的眼科表现是前缺血性视神经神经病，导致一只或两只眼睛的急性视觉丧失。在过去的十年中，我们系统地解密了GCA的免疫发育，为当前应用提供了概念框架。我们假设动脉启动的树突状细胞（DC）通过吸引，刺激和指导与疾病相关的T细胞来启动并维持血管炎。尽管健康动脉中的血管直流预防免疫刺激，但GCA中的DC具有高反应性，并损害了动脉的免疫动物。我们开发了实验系统，这些系统概括了人类动脉的微环境。人类动脉静脉嵌合体和生物工程的3-D结构类似于中型人体血管。当前的建议提出了三个特定目的，旨在机械地检查DC-T细胞相互作用，从而导致所需的T细胞耐受性或病理血管炎症。 AIM 1研究了CD28-CD86相互作用对于启动血管炎至关重要的假设。对GCA耐药的人动脉的初步研究表明，选择性抑制CD86是一种耐受性机制。采用动脉 - 霉菌嵌合体和组织工程动脉，我们将通过在DC中沉默这种costimulation Giarg的角色或用可溶性诱饵受体（CTLA4-IG）来探索CD86的作用。相反，我们将尝试通过表观遗传操作强迫CD86表达来打破耐受性。 AIM 2研究了GCA发育反映了共抑制性信号的假设，导致T细胞激活无反应。基于初步数据，显示了低表达者PD-L1启动子等位基因和GCA患者DC的PD-L1诱导不足，我们将表征有缺陷的PD-L1信号传导的机制。我们将继续临床前研究，旨在通过补充血管病变中的PD-L1来开发GCA的新疗法。 AIM 3将检查血管直流如何确定介导血管炎的T细胞效应功能。具体而言，我们将寻找调节T细胞组织侵入性的分子，这是血管炎的透壁进展的先决条件。公共卫生相关性。 GCA仍然是一种危及视力的疾病，代表了眼科紧急情况，因为可以通过及时的诊断和免疫抑制治疗来预防失明。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（所谓的树突状细胞），从而高度刺激并吸引炎性淋巴细胞。检查由炎性细胞使用的受体配体对，希望可以利用树突状细胞 - 淋巴细胞相互作用的破坏来利用这种威胁性疾病的新型治疗策略。

项目成果

Vascular dendritic cells in giant cell arteritis.

巨细胞动脉炎中的血管树突状细胞。

• DOI: 10.1196/annals.1358.023
• 发表时间: 2005
• 期刊: Annals of the New York Academy of Sciences.
• 作者: Weyand,CorneliaM;Ma-Krupa,Wei;Pryshchep,Olga;Groschel,Stefan;Bernardino,Roberto;Goronzy,JorgJ
• 通讯作者: Goronzy,JorgJ

Pathogenic principles in giant cell arteritis.

巨细胞动脉炎的致病原理。

• DOI: 10.1016/s0167-5273(00)00198-4
• 发表时间: 2000
• 期刊: International journal of cardiology
• 影响因子: 3.5
• 作者: Weyand,CM;Goronzy,JJ
• 通讯作者: Goronzy,JJ

Giant cell arteritis--a molecular approach to the multiple facets of the syndrome.

巨细胞动脉炎——针对该综合征多个方面的分子治疗方法。

• 发表时间: 1998
• 期刊: Annales de medecine interne.
• 作者: Weyand,CM;Hafner,V;Kaiser,M;Goronzy,JJ
• 通讯作者: Goronzy,JJ

Occurrence of giant cell arteritis...suddenly.

巨细胞动脉炎的发生……突然。

• 发表时间: 2007
• 期刊: Transactions of the American Ophthalmological Society
• 作者: Younge,BrianR;Weyand,CorneliaM;Goronzy,JorgJ
• 通讯作者: Goronzy,JorgJ

Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.

• DOI: 10.1084/jem.20070657
• 发表时间: 2007-10-01
• 期刊: The Journal of experimental medicine
• 作者: Guzik TJ;Hoch NE;Brown KA;McCann LA;Rahman A;Dikalov S;Goronzy J;Weyand C;Harrison DG
• 通讯作者: Harrison DG