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， 导致相当大的发病率和生活质量下降。虽有多重治未病 多发性硬化症可采用免疫调节治疗，疾病表现和治疗反应率高 在患者中是可变的和难以预测的。目前标准的护理成像技术用于诊断和 监视器MS不能提供关于个体免疫特征的早期和特定的分子信息 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并获得 任何特定患者的早期反应预测指标。因此，有必要进行非侵入性分子成像 提供关于MS中特定免疫细胞及其功能表型的实时端点的策略 病人。髓系细胞是MS进展和缓解的基础；激活的巨噬细胞和 小胶质细胞是与急性和慢性活动性中枢神经系统损害相关的主要免疫细胞。 不幸的是，现有的检测激活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)免疫反应。 为了解决这一局限性，我们最近发现在髓系细胞上表达的触发受体1(TREM1)是一种 MS小鼠模型中毒性炎症的高特异性、有前景的生物标记物，即实验性 自身免疫性脑脊髓炎(EAE)。TREM1是一种选择性表达于髓系细胞的膜受体 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。我们的初步研究表明，表达TREM1的髓系细胞数量增加 EAE小鼠的中枢神经系统(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，TREM1阳性髓系细胞的数量在 有症状的小鼠，而且似乎与四肢/尾部瘫痪的程度相关。在这里，我们假设一个 我们开发的针对TREM1的新型正电子发射断层扫描(PET)示踪剂可以用于检测和 量化多发性硬化症啮齿动物模型中髓系驱动的体内免疫反应，TREM1-PET可以 准确预测疾病进展和对治疗的反应。我们将使用 具体目标如下：1)确定TREM1-PET信号与疾病严重程度和 两种多发性硬化小鼠模型的外周炎症标志物，以及2)评估TREM1-PET对 预测和监测免疫调节疗法治疗后的结果。因此，我们的目标是建立 我们的TREM1-PET示踪剂在临床翻译前的敏感性和潜在的实用性。这项研究承诺 提供有关髓系免疫反应在体内的作用和时间进程的关键信息 EAE和MS我们提出的使用TREM1-PET的战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疾病的毒性先天免疫激活图。

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.