Vasculitis and Translational Medicine

血管炎和转化医学

• 批准号: 9563908
• 负责人: Peter Grayson
• 金额: $ 47.07万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9563908
• 关键词: American; Angiography; Animal Model; Antineutrophil Cytoplasmic Antibodies; Aortic Aneurysm; Area; Arteries; Arteritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological Markers; Blood Vessels; California; Cell Separation; Cells; Chronic Disease; Classification; Clinical; Clinical Research; Clinical Trials Database; Cocaine; Collaborations; Complex; Data; Data Analyses; Data Collection; Development; Diagnostic radiologic examination; Discipline of Nuclear Medicine; Disease; Disease Management; Disease Marker; Disease remission; Dissection; Endothelial Cells; Ethics; Etiology; Evaluation; Extramural Activities; Flow Cytometry; Foundations; Future; Gene Expression Profiling; Genetic; Goals; Gold; Helminths; Human; Hydralazine; Image; Immune; Immunologics; Immunology; In Vitro; Inflammation; International; Intramural Research; Laboratories; Levamisole; Life; Metabolism; Modeling; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Drug Abuse; Natural History; Nervous system structure; North America; Organ; Outcome; Outcome Measure; Pathogenesis; Patient Recruitments; Patients; Pharmaceutical Preparations; Physicians; Play; Polychondritis; Population; Positron-Emission Tomography; Procainamide; Protocols documentation; Publications; Publishing; Randomized Clinical Trials; Rare Diseases; Recording of previous events; Recruitment Activity; Relapse; Research; Rheumatology; Role; Sampling; San Francisco; Source; Standardization; Steroids; Suggestion; Surface; Systemic Lupus Erythematosus; Systemic disease; Techniques; Temporal Arteritis; Tissues; Translational Research; United States; United States National Institutes of Health; Universities; Vascular Endothelial Cell; Vasculitis; Work; activity marker; aged; biobank; biomarker discovery; cholinergic; cocaine exposure; cocaine use; cohort; college; experimental study; extracellular; imaging biomarker; immunogenicity; insight; meetings; neutrophil; new therapeutic target; novel; novel marker; novel therapeutics; patient advocacy group; patient subsets; personalized medicine; predictive of treatment response; programs; research clinical testing; transcriptome sequencing; translational medicine; translational research program; vascular abnormality; vascular inflammation; whole genome; working group

Summary: Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused upon three forms of vasculitis: drug-induced vasculitis, large vessel vasculitis (LVV), and relapsing polychondritis (RP). In terms of drug-induced vasculitis, we have focused on levamsiole, an anti-helminth drug that has recently been implicated in cases of drug-induced autoimmunity in humans exposed to cocaine adulterated with levamisole for profit. The United States Drug Enforcement Agency estimates that approximately 75% of cocaine within the US has been contaminated with levamisole. We discovered that levamisole induces neutrophil extracellular trap (NET) formation through engagement of muscarinic receptors on the surface of neutrophils. Through animal models we defined that the M3 muscarinic receptor specifically is triggered by levamisole. In collaboration with colleagues from the National Institute of Drug Abuse and colleagues from the University of California, San Francisco, we studied sera from cohorts of patients actively using cocaine contaminated with levamisole to identify novel autoantibodies against NET components. We also studied the effects of levamisole and NETs on vascular endothelial cells and found that levamisole-induced NETs were toxic to endothelial cells in vitro and in aortic myogram models. These data suggest that NETs are a source of autoantigens in levamisole-induced autoimmunity, contribute to vascular damage, and that heretofore uncharacterized interactions between the cholinergic nervous system and neutrophils may play a causal role in autoantibody formation and autoimmune disease. This work was published in JCI Insight in February 2017. In terms of LVV, we continue to recruit patients with these rare diseases. To date, we have performed whole body PET scans and angiography on approximately 80 patients with LVV. We have discovered vascular abnormalities on PET scans suggestive of ongoing subclinical vascular inflammation in a subset of patients with LVV (approximately 50%) who clinically were thought to be in disease remission. These findings are intriguing because a subset of patients with LVV are known to develop life-threatening vascular complications including aortic aneurysms and dissections late into the course of disease. The first publication from this work is currently under revision. Four imaging abstracts from this cohort were submitted to the 2017 American College of Rheumatology Annual Meeting. In the lab, we are studying the immunology of subclinical vascular inflammation in LVV. Preliminary findings from in vitro studies indicate that metabolism is altered in specific immune cell populations in association with PET scan findings in patients with LVV. In a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We are analyzing data from RNA sequencing experiments on the different cell populations in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets. In terms of relapsing polychondritis, we have recruited 35 patients with this rare disease. We are currently developing classification criteria for this disease and defining an optimal clinical approach to assessment and treatment of this condition. As part of these efforts, we have formed the first International Working Group in Relapsing Polychondritis, dedicated to collaborative clinical and translational research in this disease.

总结： 迄今为止，血管炎自然史研究中的招募仍然很强。所有在NIH临床中心就诊的患者都接受了全面的临床评估，并将样本贡献给不断增长的生物库。在过去的一年里，我们集中在三种形式的血管炎：药物引起的血管炎，大血管炎（LVV），复发性多囊炎（RP）。 在药物引起的血管炎方面，我们重点关注左旋咪唑，这是一种抗蠕虫药物，最近被发现与暴露于掺杂左旋咪唑的可卡因的人类药物诱导的自身免疫性病例有关。美国缉毒署估计，美国境内约75%的可卡因被左旋咪唑污染。我们发现左旋咪唑通过与中性粒细胞表面的毒蕈碱受体结合诱导中性粒细胞胞外陷阱（NET）的形成。通过动物模型，我们确定M3毒蕈碱受体特异性地被左旋咪唑触发。我们与国家药物滥用研究所的同事和加州大学旧金山分校弗朗西斯科的同事合作，研究了积极使用左旋咪唑污染的可卡因的患者队列的血清，以鉴定针对NET成分的新型自身抗体。我们还研究了左旋咪唑和NETs对血管内皮细胞的影响，发现左旋咪唑诱导的NETs在体外和主动脉肌电模型中对内皮细胞具有毒性。这些数据表明，NET是左旋咪唑诱导的自身免疫中的自身抗原的来源，有助于血管损伤，并且迄今未表征的胆碱能神经系统和中性粒细胞之间的相互作用可能在自身抗体形成和自身免疫性疾病中发挥因果作用。这项工作于2017年2月发表在JCI Insight上。 在LVV方面，我们继续招募这些罕见病患者。迄今为止，我们已经对大约80名LVV患者进行了全身PET扫描和血管造影。我们在PET扫描中发现了血管异常，提示在临床上被认为处于疾病缓解期的LVV患者亚组（约50%）中存在持续的亚临床血管炎症。这些发现是有趣的，因为已知LVV患者的一个子集在病程后期会发生危及生命的血管并发症，包括主动脉瘤和夹层。这项工作的第一份出版物目前正在修订中。来自该队列的四篇成像摘要提交给了2017年美国流变学学会年会。在实验室中，我们正在研究LVV亚临床血管炎症的免疫学。体外研究的初步结果表明，LVV患者中特定免疫细胞群的代谢改变与PET扫描结果相关。在我们队列中的一部分LVV患者中，我们继续使用细胞分选技术纯化免疫细胞群。我们正在分析来自不同细胞群的RNA测序实验的数据，并将其与放射学和临床结果相关联，以发现疾病活动的新标志物和潜在的新治疗靶点。 在复发性多囊炎方面，我们招募了35名患有这种罕见疾病的患者。我们目前正在制定这种疾病的分类标准，并确定评估和治疗这种疾病的最佳临床方法。作为这些努力的一部分，我们成立了第一个复发性息肉病国际工作组，致力于这种疾病的合作临床和转化研究。