Locke Landon W, Kothandaraman Shankaran, Tweedle Michael, Chaney Sarah, Wozniak Daniel J, Schlesinger Larry S
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, 793 Biomedical Research Tower, 460 W. 12th Avenue, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Department of Radiology, The Wright Center for Innovation in Biomedical Imaging, Martha Morehouse Medical Plaza, 2050 Kenny Road, The Ohio State University, Columbus, OH 43221, USA.
Tuberculosis (Edinb). 2018 Jan;108:201-210. doi: 10.1016/j.tube.2018.01.001. Epub 2018 Jan 8.
Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma. We report the binding specificity of Cyanine 3 (Cy3)-labeled cFLFLFK-PEG to human leukocytes and cellular constituents within a human in vitro granuloma model. We also report use of the probe in in vivo studies using a mouse model of lung granulomatous inflammation. We found that the probe preferentially binds human neutrophils and macrophages in human granuloma structures. Inhibition studies showed that peptide binding to human neutrophils is mediated by the receptor formyl peptide receptor 1 (FPR1). Imaging the distribution of intravenously administered cFLFLFK-PEG-Cy3 in the mouse model revealed probe accumulation within granulomatous inflammatory responses in the lung. Further characterization revealed that the probe preferentially associated with neutrophils and cells of the monocyte/macrophage lineage. As there is no current clinical diagnostic imaging tool that specifically targets granulomas, the use of this probe in the context of latent and active TB may provide a unique advantage over current clinical imaging probes. We anticipate that utilizing a FPR1-targeted radiopharmaceutical analog of cFLFLFK in preclinical imaging studies may greatly contribute to our understanding of granuloma influx patterns and the biological roles and consequences of FPR1-expressing cells in contributing to disease pathogenesis.
肉芽肿是结核病（TB）潜伏和活动期的组织病理学标志。尚未开发出专门针对肉芽肿的诊断和治疗策略。我们的目标是开发一种用于对浸润肉芽肿的相关免疫细胞群体进行成像的探针。我们报告了菁染料CY3（Cy3）标记的cFLFLFK-聚乙二醇（PEG）对人白细胞和人体外肉芽肿模型中的细胞成分的结合特异性。我们还报告了该探针在使用肺肉芽肿性炎症小鼠模型的体内研究中的应用。我们发现该探针优先与人肉芽肿结构中的人中性粒细胞和巨噬细胞结合。抑制研究表明，肽与人中性粒细胞的结合是由甲酰肽受体1（FPR1）介导的。对小鼠模型中静脉注射的cFLFLFK-PEG-Cy3的分布进行成像，显示探针在肺部肉芽肿性炎症反应中积聚。进一步的表征表明，该探针优先与中性粒细胞和单核细胞/巨噬细胞谱系的细胞相关联。由于目前没有专门针对肉芽肿的临床诊断成像工具，在潜伏性和活动性结核病的背景下使用该探针可能比目前的临床成像探针具有独特优势。我们预计，在临床前成像研究中使用cFLFLFK的FPR1靶向放射性药物类似物可能会极大地有助于我们了解肉芽肿的流入模式以及表达FPR1的细胞在疾病发病机制中的生物学作用和后果。
