Molecular Imaging CCR2 Lung Inflammation and Fibrosis

摘要 肺纤维化是一种知之甚少的、难以诊断的细胞反应失调的结果。 还有款待。一种常见的形式，特发性肺纤维化(IPF)，有一个渐进的，下坡的过程。没有 用于诊断、治疗或疾病活动性的成熟的分子生物标志物。临床医生目前依赖于 对胸部CT和肺功能的变化进行监测。此外，还有 只有两种被批准的药物疗法，治疗不是由分子生物标记物指导的。肺CCR2+(C-C 基序趋化因子受体2)炎性单核细胞及其病理后代间质巨噬细胞 与实验性肺纤维化的发展密切相关，在慢性阻塞性肺疾病患者的肺中升高。 肺纤维化，并产生促纤维化因子。CCR2基因缺失小鼠的纤维化显著减轻，并通过 CCR2+子代巨噬细胞的缺失，有力地支持了CCR2+细胞在人类疾病中的作用。这 该提案旨在利用基于分子正电子发射断层扫描(PET)的诊断来检测CCR2- 介导纤维化患者肺部炎症，并开发有针对性的治疗方法。我们的 多学科小组已经证实，一种基于多肽的放射性示踪剂64Cu-DOTA-ECL1i可以识别CCR2+ 动物模型中的单核细胞，在我们最近的PET/CT人类0/1期试验中具有可接受的剂量学特征 成像。CCR2+细胞与肺纤维化的已知关系及临床处理挑战 IPF患者，使这种疾病特别适合于评估放射性示踪剂。因此，我们使用了 多种小鼠肺纤维化模型显示64Cu-DOTA-ECL1i肺摄取增加与 CCR2+细胞浸润和纤维化。我们的数据还显示，放射性示踪剂检测到肺摄取减少 阻断CCR2+细胞中表达的纤维化介质白介素1b后，博莱霉素诱导的纤维化 使用抗纤维化药物吡非尼酮治疗。IPF患者的Pilot CCR2-PET成像显示肺增加 信号，特别是在胸膜下纤维化区。我们建议使用64Cu-DOTA-ECL1i PET成像来 在动物模型中评价CCR2+特异性炎症在纤维化肺疾病过程中的调节作用 验证人肺组织中CCR2细胞的检测，并评估监测患者的潜力。我们 假设64Cu-DOTA-ECL1i检测到与肺相关的CCR2+细胞炎症过程 纤维化，并可用于监测疾病的活动。具体目标是：(1)在小鼠纤维化模型中，评估 临床治疗后炎症和纤维化与64Cu-DOTA-ECL1i PET/CT摄取的变化 抗纤维化药物和CCR2拮抗剂的分子靶向，以及(2)在IPF患者中，评估 PET摄取与CT影像、临床状态的关系，验证PET摄取与CT的关系 移植后去除肺中CCR2介导的炎症和促纤维化基因表达的摄取。 总之，AIMS提供了一个获取与CCR2+细胞基础相关的详细信息的平台 IPF的成像和对可能导致IPF靶向分子疗法的人体研究的解释。

SUMMARY Pulmonary fibrosis is the result of a poorly understood, dysregulated cellular response that is difficult to diagnose and treat. A common form, idiopathic pulmonary fibrosis (IPF), has a progressive, downhill course. There are no well-established molecular biomarkers for diagnosis, treatment, or disease activity. Clinicians currently depend on changes in chest computed tomography (CT) and pulmonary function to monitor patients. Moreover, there are only two approved drug therapies, and treatment is not guided by molecular biomarkers. Lung CCR2+ (C-C motif chemokine receptor 2) inflammatory monocytes and their pathologic progeny, interstitial macrophages, are strongly associated with the experimental development of lung fibrosis, elevated in the lungs of patients with pulmonary fibrosis, and produce profibrotic factors. Fibrosis is significantly attenuated in Ccr2 null mice and by deletion of CCR2+ progeny macrophages, strongly supporting a role for CCR2+ cells in human disease. This proposal aims to utilize a molecular, positron-emission tomography (PET)-based diagnostic to detect CCR2- mediated inflammation in the lungs of patients with fibrosis and to develop targeted therapies. Our multidisciplinary group has established that a peptide-based radiotracer, 64Cu-DOTA-ECL1i, identifies CCR2+ monocytes in animal models and has acceptable dosimetry in our recent human Phase 0/1 trial of PET/CT imaging. The known relationship of CCR2+ cells to pulmonary fibrosis and the clinical challenges of managing patients with IPF, make this disease particularly suited for evaluating the radiotracer. Therefore, we have used multiple mouse models of lung fibrosis to show that increased 64Cu-DOTA-ECL1i lung uptake correlates with CCR2+ cell infiltration and fibrosis. Our data also show that the radiotracer detects decreases in lung uptake in bleomycin-induced fibrosis after blockade of interleukin-1b, a mediator of fibrosis expressed in CCR2+ cells, and treatment with anti-fibrotic drug, pirfenidone. Pilot CCR2-PET imaging of patients with IPF show increased lung signal, particularly in regions of subpleural fibrosis. We propose to use 64Cu-DOTA-ECL1i PET imaging to evaluate modulation of CCR2+-specific inflammation during the course of fibrotic lung disease in animal models, validate the detection of CCR2 cells in human lung tissue, and assess the potential for monitoring patients. We hypothesize that 64Cu-DOTA-ECL1i detects the CCR2+ cell inflammatory process associated with pulmonary fibrosis and can be used to monitor disease activity. Specific aims are: (1) In mouse fibrosis models, assess the change in the 64Cu-DOTA-ECL1i PET/CT uptake relative to inflammation and fibrosis upon treatment with clinical anti-fibrotic drugs and following molecular targeting with CCR2 antagonists, and (2) In patients with IPF, assess the relationship between PET uptake, CT imaging, and clinical status, then validate the relationship of PET uptake with CCR2-mediated inflammation and pro-fibrotic gene expression in lungs removed after transplant. Together, the aims provide a platform to obtain detailed information related to the underpinnings of CCR2+ cell imaging in IPF and the interpretation of human studies that may lead to targeted molecular therapies for IPF.