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