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

项目摘要 多发性硬化症（MS）是一种慢性、脱髓鞘、神经炎性疾病，通常影响年轻人， 导致严重的发病率和生活质量下降。虽然多种疾病修饰 免疫调节疗法可用于MS，疾病表现和治疗反应是高度相关的。 在患者中变量和难以预测。目前用于诊断和治疗的标准成像技术 监测MS不能提供关于个体免疫特征的早期和特异性分子信息 在中枢神经系统（CNS），从而限制了我们选择最合适的治疗方法， 任何特定患者的早期反应预测因子。因此，需要非侵入性分子成像 提供关于MS中特定免疫细胞及其功能表型的实时终点的策略 患者骨髓细胞是MS进展和缓解的基础;活化的巨噬细胞和巨噬细胞是MS的基础。 小胶质细胞是与急性和慢性活动性CNS病变相关的主要免疫细胞。 不幸的是，现有的用于检测活化的小胶质细胞和巨噬细胞的成像策略缺乏特异性 并且不能区分有益（抗炎）和毒性（促炎）免疫应答。 为了解决这一局限性，我们最近鉴定了髓样细胞表达的触发受体1（TREM 1）， MS小鼠模型中毒性炎症的高度特异性、有希望的生物标志物，即，实验 自身免疫性脑脊髓炎（EAE）。TREM 1是一种选择性表达于骨髓的膜受体 谱系细胞，已知通过与经典模式协同作用而加剧促炎反应 识别受体我们的初步研究显示，在急性白血病患者中，表达TREM 1的髓样细胞数量增加， EAE小鼠的CNS（与对照组相比）在疾病的非常早期阶段，在临床发展之前， 症状此外，TREM 1阳性髓样细胞的数量以甚至更高的水平存在， 症状的小鼠，并且似乎与肢体/尾部麻痹的程度相关。在这里，我们假设， 我们开发的靶向TREM 1的新型正子发射断层扫描（PET）示踪剂可用于检测和 量化啮齿类MS模型中骨髓驱动的体内免疫应答，并且TREM 1-PET可以 准确预测疾病进展和对治疗的反应。我们将测试我们的假设与 1）确定TREM 1-PET信号、疾病严重程度和预后之间的关系。 2）评估TREM 1-PET在MS的两种小鼠模型中的炎症外周标志物，和 预测和监测免疫调节治疗后的结果。因此，我们的目标是建立 我们的TREM 1-PET示踪剂在临床转化之前的灵敏度和潜在效用。这项研究承诺， 提供关于骨髓驱动的免疫应答的作用和时间过程的关键体内信息， EAE和MS。我们提出的使用TREM 1-PET的策略可能会产生深远而重大的影响， 分子成像技术用于绘制一系列神经系统疾病中的毒性先天免疫激活。

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.