Chemokine Receptor 2-targeted Molecular Imaging in Pulmonary Fibrosis A Clinical Trial
Chemokine Receptor 2-targeted Molecular Imaging in Pulmonary Fibrosis A Clinical Trial
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DOI：
10.1164/rccm.202004-1132oc
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发表时间：
2021-01-01
影响因子：
24.7
通讯作者：
Liu, Yongjian
中科院分区：
文献类型：
--
作者：
Brody, Steven L.;Gunsten, Sean P.;Liu, Yongjian
基本原理：特发性肺纤维化（IPF）是一种进行性炎症性肺病，没有疾病活动或治疗反应的有效分子标志物。表达C-C基序CCR 2的单核细胞和间质巨噬细胞目的：为了对IPF患者进行潜在的靶向治疗，我们开发了Cu-64-DOTA-ECL 1 i，一种放射性示踪剂，用于使用正电子发射断层扫描（PET）非侵入性地追踪CCR 2（+）单核细胞和巨噬细胞。在博莱霉素或放射诱导的纤维化小鼠和IPF人类受试者中研究了CCR 2（+）细胞。将CCR 2（+）细胞群体相对于肺组织中的纤维化区域定位，并使用免疫定位、单细胞质量细胞术和Ccr 2 RNA原位杂交进行表征，然后与通过Cu-64-DOTA-ECL 1 i PET进行的肺摄取的平行定量相关联。小鼠模型建立了肺中Cu-64-DOTA-ECL 1 i PET摄取增加与纤维化相关的CCR 2（+）细胞浸润相关（n = 72）。作为治疗模型，通过IL 1 β阻断（n = 19）或抗纤维化吡非尼酮（n = 18）抑制纤维化可减少小鼠肺中CCR 2（+）巨噬细胞蓄积和放射性示踪剂摄取。在IPF患者的肺组织中，CCR 2（+）细胞集中在纤维化周围区域，并与放射性示踪剂定位相关（n = 21）。人体成像显示健康志愿者（n = 7）的肺摄取很少，而IPF受试者（n = 4）在纤维化区域显示出强烈的信号。结论：这些发现支持了对IPF纤维化小生境中的CCR 2（+）细胞进行成像的作用，为个性化治疗和监测提供了分子靶点。
Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis.Objectives: To phenotype patients with IPF for potential targeted therapy, we developed Cu-64-DOTA-ECL1i, a radiotracer to noninvasively track CCR2(+) monocytes and macrophages using positron emission tomography (PET).Methods: CCR2(+) cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2(+) cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by Cu-64-DOTA-ECL1i PET.Measurements and Main Results: Mouse models established that increased Cu-64-DOTA-ECL1i PET uptake in the lung correlates with CCR2(+) cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL1 beta blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR2(+) macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2(+) cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones.Conclusions: These findings support a role for imaging CCR2(+) cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.