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.

摘要 免疫细胞的激活是神经退行性疾病发生和发展的关键过程， 尤其是多发性硬化症。目前，还没有一种非侵入性成像方法可以特定地 在临床环境中检测激活的免疫细胞和神经炎症。 用于正电子发射断层扫描(PET)的放射性示踪剂的最新发展显示出巨大的潜力 检测来自适应性免疫系统的细胞。具体地，2‘-脱氧-2’-[18F]氟-9-β-D- 阿拉伯呋喃核苷([18F]F-Arag)已被证明能够检测到活化的初级T细胞 移植物抗宿主病。同时，超极化13C磁共振波谱成像(HP 13C-MRSI)是一种新的实时监测体内酶反应的代谢磁共振方法。惠普 [1-13C]丙酮酸已被证明对来自先天免疫的高度糖酵解促炎细胞敏感 外周炎症、多发性硬化症和创伤性脑损伤动物模型中的巨噬细胞。 重要的是，[18F]F-Arag和HP[1-13C]丙酮酸在首次人类研究中都显示出巨大的希望。 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 一项新的非侵入性评估脑损害分期和监测免疫调节治疗反应的研究 MS的小鼠模型 为此，将在疾病诱导的关键时间点进行HP 13C MRSI和PET成像 和进步。接下来，将使用HP[1-13C]丙酮酸和[18F]F-Arag来评估 两种临床上相关的治疗多发性硬化症的常用药物，富马酸二甲酯和芬格莫特。PET和核磁共振 这些发现将通过体外示踪剂生物分布和免疫组织病理学标记物的相关性来证实 用于炎症和病变特征描述。 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 成像结果，该项目的结果将确定临床相关的生物标记物，可以提供 诊断、预后和治疗信息，更好地实现MS患者的精准医学 在临床翻译时，这些方法可以帮助改进治疗方案，并导致更好的临床 结果和患者的生活质量。