Imaging innate and adaptive immune response in MS using using [18F]F-AraG PET and hyperpolarized 13C MRSI

使用 [18F]F-AraG PET 和超极化 13C MRSI 对 MS 中的先天性和适应性免疫反应进行成像

• 批准号: 10040874
• 负责人: Myriam Marianne Chaumeil
• 金额: $ 28.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040874
• 关键词: Adaptive Immune System; Anatomy; Animal Model; Animals; Appearance; Autopsy; Biochemical Reaction; Biodistribution; Biological Markers; Biopsy; Brain; Brain region; Cells; Cerebrum; Clinical; Clinical Management; Cognitive; Cuprizone; Detection; Development; Diagnostic; Disease; Disease Progression; Drug Evaluation; Drug Prescriptions; Effectiveness; Enzymes; Etiology; Experimental Autoimmune Encephalomyelitis; FDA approved; Fumarates; Goals; Heart; Human; Image; Immune; Immune response; Immunologic Monitoring; Immunomodulators; In Situ; Inflammation; Inflammatory; Inflammatory Arthritis; Innate Immune System; Joints; Kinetics; Lactate Dehydrogenase; Lead; Lesion; Lesion by Stage; Link; Liver; Lung; Lymphocyte; Magnetic Resonance Imaging; Maintenance; Malignant Neoplasms; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; Monitor; Motor; Multiple Sclerosis; Multiple Sclerosis Lesions; Neuraxis; Neurodegenerative Disorders; Organ; Outcome; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Positron-Emission Tomography; Process; Pyruvate; Quality of life; Regimen; Research; Role; Signal Transduction; Squamous Cell; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Time; Tissues; Tracer; Traumatic Brain Injury; Tumor-infiltrating immune cells; adaptive immune response; base; cancer cell; clinical examination; clinical translation; clinically relevant; clinically translatable; drug efficacy; first-in-human; graft vs host disease; healthy volunteer; human study; imaging approach; imaging detection; imaging modality; imaging study; immune activation; immunomodulatory therapies; immunoregulation; improved; in vivo; in vivo monitoring; inflammatory marker; macrophage; magnetic resonance spectroscopic imaging; mouse model; multiple sclerosis patient; neuroimaging; neuroinflammation; non-invasive imaging; non-invasive monitor; novel; pathogen; precision medicine; prognostic; pyruvate dehydrogenase; radiotracer; response; treatment response

ABSTRACT Activation of immune cells is a key process in the initiation and progression of neurodegenerative diseases, particularly multiple sclerosis (MS). Presently, there is no non-invasive imaging method that can specifically detect activated immune cells and neuroinflammation in clinical settings. Recent development of radiotracers for positron emission tomography (PET) have shown great potential for the detection of cells from the adaptive immune system. Specifically, 2'-deoxy-2'-[18F]fluoro-9-β-D- arabinofuranosylguanine ([18F]F-AraG) has been shown to enable the detection of activated primary T-cells in graft-versus-host disease. At the same time, hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is emerging as a new metabolic MR method to monitor enzymatic reactions in vivo in real-time. HP [1-13C] pyruvate has proven to be sensitive to highly glycolytic pro-inflammatory cells from the innate immune system (i.e. Macrophages) in animal models of peripheral inflammation, MS and traumatic brain injury. Importantly, both [18F]F-AraG and HP [1-13C] pyruvate have shown great promise in first-in-human studies of cancer. In this project, we propose to investigate the potential of HP [1-13C] pyruvate and [18F]F-AraG PET imaging to non-invasively assess cerebral lesion stage and to monitor response to immunomodulatory therapies in a novel murine model for MS. To do so, HP 13C MRSI and PET imaging sessions will be performed at key time points during disease induction and progression. Next, HP [1-13C] pyruvate and [18F]F-AraG will be used to evaluate treatment response from two clinically relevant and commonly prescribed drugs for MS, Dimethyl-fumarate and Fingolimod. PET and MRI findings will be confirmed using ex vivo correlates of tracer biodistribution and immuno-histopathological markers for inflammation and lesion characterization. Because HP [1-13C] pyruvate and [18F]F-AraG PET are readily available for clinical translation, drugs and the imaging findings, outcomes from this project will identify clinically relevant biomarkers that could provide diagnostic, prognostic and therapeutic information to better achieve precision medicine for patients with MS. Upon clinical translation, such methods could help refine therapeutic regimens and lead to better clinical outcomes and patient quality of life.

抽象的 免疫细胞的激活是神经退行性疾病的主动性和进展的关键过程， 特别是多发性硬化症（MS）。目前，没有非侵入性成像方法可以专门 在临床环境中检测到的活化的免疫细胞和神经炎症。 阳性发射断层扫描（PET）的放射性示踪剂的最新发展显示出很大的潜力 从适应性免疫系统中检测细胞。具体而言，2'-Deoxy-2' - [18F]氟-9-β-d- 已证明阿拉伯呋喃糖基瓜（[18F] F-arag）可以检测活化的原代T细胞 移植物与宿主病。同时，超极化13C磁共振光谱成像（HP 13C MRSI）正在成为一种新的代谢MR方法，可实时监测体内酶促反应。惠普 [1-13C]丙酮酸已被证明对先天免疫的高糖酵解促炎细胞很敏感 周围感染，MS和创伤性脑损伤的动物模型中的系统（即巨噬细胞）。 重要的是，[18F] F-ARAG和HP [1-13C]丙酮酸都在人类的首次人类研究中都表现出巨大的希望 癌症。 在这个项目中，我们建议研究HP [1-13C]丙酮酸和[18F] F-arag PET成像的潜力 非侵入性评估脑病变阶段，并监测新颖的免疫调节疗法的反应 MS的鼠模型。 为此，HP 13C MRSI和PET成像会议将在疾病诱导期间的关键时间点进行 和进展。接下来，HP [1-13C]丙酮酸和[18F] F-ARAG将用于评估从 MS，二甲基二甲酯和芬洛莫德的两种临床相关和常规药物。宠物和MRI 调查结果将使用示踪剂生物分布和免疫 - 涉及病理学标记的离体相关性确认 用于炎症和病变表征。 因为HP [1-13C]丙酮酸和[18F] F-Arag PET很容易用于临床翻译，药物和 成像发现，该项目的结果将确定可以提供的临床相关生物标志物 诊断，预后和治疗信息，以更好地为MS患者获得精确药物。 临床翻译后，这种方法可以帮助改善热方案并导致更好的临床 结果和患者生活质量。