Tracking the invaders in multiple sclerosis: Highly specific TREM1-targeted PET imaging of toxic infiltrating myeloid cells and early treatment response.

追踪多发性硬化症中的入侵者：毒性浸润骨髓细胞的高度特异性 TREM1 靶向 PET 成像和早期治疗反应。

• 批准号: 9651665
• 负责人: Katrin I. Andreasson
• 金额: $ 19.58万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9651665
• 关键词: Acute; Address; Affect; Aftercare; Anti-inflammatory; Area; Autoradiography; Binding; Biological Markers; Bone Marrow; Brain; Cell Lineage; Cells; Chronic; Chronic Progressive Multiple Sclerosis; Clinical; Clinical Trials; Detection; Diagnosis; Disadvantaged; Disease; Disease Marker; Disease Progression; Disease remission; Early Diagnosis; Early treatment; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Future; Goals; Housing; Image; Imaging Techniques; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Lesion; Limb structure; Location; Magnetic Resonance Imaging; Measures; Mediating; Membrane; Methods; Microglia; Modeling; Molecular; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Multiple Sclerosis; Mus; Myelogenous; Myeloid Cells; Neuraxis; Outcome; Paralysed; Patients; Pattern recognition receptor; Peripheral; Phenotype; Plasma; Positron-Emission Tomography; Proteins; Quality of life; Radiolabeled; Relapsing-Remitting Multiple Sclerosis; Research; Rodent Model; Role; Selection for Treatments; Severity of illness; Signal Transduction; Specificity; Spinal Cord; Spleen; Surrogate Endpoint; Symptoms; Tail; Testing; Therapeutic; Time; Tissue Harvesting; Tissues; Tracer; Translations; biomarker-driven; central nervous system demyelinating disorder; clinical development; clinical translation; cost; cytokine; disability; functional status; imaging agent; imaging biomarker; imaging modality; immune activation; immunomodulatory drugs; immunomodulatory therapies; in vivo; individualized medicine; inflammatory marker; macrophage; molecular imaging; mouse model; multiple sclerosis patient; nervous system disorder; neuroinflammation; novel; patient population; patient stratification; predicting response; receptor; response; selective expression; standard of care; tomography; treatment response; young adult

Project Summary Multiple sclerosis (MS) is a chronic, demyelinating, neuroinflammatory disease typically affecting young adults, causing substantial morbidity and diminished quality of life. Although multiple disease-modifying immunomodulatory therapies are available for MS, disease manifestations and treatment response are highly variable and difficult to predict in patients. Current standard of care imaging techniques used to diagnose and monitor MS cannot provide early and specific molecular information regarding an individual’s immune signature in the central nervous system (CNS), thus limiting our ability to select the most appropriate therapy and obtain early predictors of response for any given patient. Hence there is a need for non-invasive molecular imaging strategies that provide real-time endpoints about specific immune cells and their functional phenotypes in MS patients. Myeloid cells are fundamental to the progression and remission of MS; activated macrophages and microglia are the predominant immune cells associated with acute and chronic-active CNS lesions. Unfortunately, existing imaging strategies for detecting activated microglia and macrophages lack specificity and cannot distinguish between beneficial (anti-inflammatory) and toxic (pro-inflammatory) immune responses. To address this limitation, we recently identified triggering receptor expressed on myeloid cells 1 (TREM1) as a highly specific, promising biomarker of toxic inflammation in a mouse model of MS, i.e., experimental autoimmune encephalomyelitis (EAE). TREM1 is a membrane receptor selectively expressed on myeloid lineage cells, known to exacerbate pro-inflammatory responses by synergizing with classical pattern recognition receptors. Our preliminary studies show elevated numbers of TREM1-expressing myeloid cells in the CNS of EAE mice (compared to controls) at very early stages of disease prior to the development of clinical symptoms. Moreover, the numbers of TREM1-positive myeloid cells are present at even higher levels in symptomatic mice, and appear to correlate with degrees of limb/tail paralysis. Here, we hypothesize that a novel positon emission tomography (PET) tracer we developed to target TREM1 can be used to detect and quantify in vivo myeloid-driven immune responses in rodent models of MS, and that TREM1-PET can accurately predict disease progression and response to therapies. We will test our hypothesis with the following specific aims: 1) To determine the relationship between TREM1-PET signal, disease severity, and peripheral markers of inflammation in two mouse models of MS, and 2) To assess the ability of TREM1-PET to predict and monitor outcomes after treatment with immunomodulatory therapeutics. We thus aim to establish the sensitivity and potential utility of our TREM1-PET tracer prior to clinical translation. This research promises to provide critical in vivo information about the role and time course of myeloid-driven immune responses in EAE and MS. Our proposed strategy using TREM1-PET could have far-reaching and significant impact as a molecular imaging technique for mapping toxic innate immune activation in a range of neurological diseases.

项目摘要 多发性硬化症（MS）是一种慢性，脱髓鞘，神经炎症性疾病，通常会影响年轻人， 导致大量发病率和生活质量下降。虽然多种疾病调整 免疫调节疗法可用于MS，疾病表现和治疗反应高度 患者可变且难以预测。用于诊断和 Monitor MS无法提供有关个人免疫签名的早期和特定分子信息 在中枢神经系统（CNS）中，从而限制了我们选择最合适疗法的能力并获得 任何给定患者的反应的早期预测指标。因此需要非侵入性分子成像 提供有关特定免疫细胞及其功能表型的实时终点的策略 患者。髓样细胞对于MS的进展和缓解至关重要。活化的巨噬细胞和 小胶质细胞是与急性和慢性CNS病变有关的主要免疫细胞。 不幸的是，检测活化的小胶质细胞和巨噬细胞的现有成像策略缺乏特异性 并且无法区分有益的（抗炎）和有毒（促炎性）免疫复杂。 为了解决这一局限 在MS的小鼠模型中，高度特异性，有前途的有毒注射生物标志物，即实验 自身免疫性脑脊髓炎（EAE）。 TREM1是膜接收器，在髓样中有选择地表达 谱系细胞，已知通过与经典模式协同作用加剧促炎反应 识别受体。我们的初步研究表明，在 在临床发展之前，EAE小鼠的中枢神经系统（与对照组相比）在疾病的早期阶段 症状。此外，trem1阳性髓样细胞的数量在更高的水平中存在 有症状的小鼠，似乎与肢体/尾部瘫痪程度相关。在这里，我们假设 我们开发用于靶向trem1的新型二极化发射断层扫描（PET）示踪剂可用于检测和 在MS的啮齿动物模型中量化体内髓样驱动的免疫回报，并且Trem1-Pet可以 准确预测疾病的进展和对疗法的反应。我们将通过 以下具体目的：1）确定trem1-pet信号，疾病严重程度和 两种MS小鼠模型中炎症的外围标记和2）评估Trem1-Pet的能力 通过免疫调节治疗治疗后预测和监测结果。因此，我们旨在建立 在临床翻译之前，我们的Trem1-Pet示踪剂的灵敏度和潜在效用。这项研究有望 提供有关髓样驱动的免疫反应的作用和时间过程的关键体内信息 EAE和MS。我们使用trem1-pet的拟议策略可能具有深远的影响和重大影响 用于在一系列神经疾病中绘制有毒先天免疫激活的分子成像技术。