Concurrent tracking of the trafficking of individual immune cell populations after myocardial infarction (MI) by ‘multicolor’ 1H/19F MRI

通过“多色”1H/19F MRI 同步跟踪心肌梗塞 (MI) 后个体免疫细胞群的运输

• 批准号: 330470715
• 负责人: Professor Dr. Ulrich Flögel
• 金额: --
• 依托单位: Institut für Molekulare Kardiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/330470715?language=en
• 关键词: Concurrent; tracking; trafficking; individual; immune

19F MRI has proven to be an excellent tool for background-free imaging of inflammation. For this, emulsified perfluorocarbons (PFCs) are injected, which are preferentially phagocytized by circulating monocytes that can be detected by 1H/19F MRI after infiltration into inflammatory foci. However, also B-cells, dendritic cells or neutrophils can internalize PFCs under certain conditions and small-sized PFCs may passively diffuse into inflammatory lesions via a leaky endothelium. Thus, the detected 19F signal is derived from a complex mixture of cells which were labelled in the bloodstream and/or locally internalized the PFCs. Lately, we advanced the 19F MRI approach by directing ligand-equipped PFCs to specific epitopes enabling an active targeting of individual cell populations. Furthermore, we developed an imaging technique for concurrent detection of different PFCs with distinct spectral signatures allowing the simultaneous visualization of several targets. To overcome the described limitations, this proposal is aimed at expanding the current approach for:1) Specific targeting of neutrophils, classical/non-classical monocytes and CD4+ T-cells: For this, we will generate PFCs to specifically label the distinct cell types within the bloodstream and implement a ‘multicolor’ 19F compressed sensing technique to enhance the detection thresholds. We already revealed a targeting peptide for neutrophils and will identify novel ligands against both monocyte subsets using phage display screening. CD4+ T-cells will be targeted by anti-CD4 mAb/mAb-derivatives and/or by a novel transgenic mouse with specific PFC internalization properties of CD4+ T-cells. 2) Tracking sequential immune cell infiltration and alterations in tissue texture after MI: Monitoring the infiltration of neutrophils, classical/non-classical monocytes and CD4+ T-cells into the heart after MI will enable a precise mapping of the quality of the current inflammatory state. In combination with multiparametric 1H MRI (T1, T2, CEST), this allows a comprehensive characterization of local inflammation and associated alterations in tissue textures. To address interorgan crosstalk also bone marrow, spleen, kidney and lung are included into the imaging protocol which will provide insight in the overall immune cell trafficking after MI. With this approach, we will furthermore investigate how an altered immunological predisposition will impact on the outcome after MI. In summary, this approach will permit (i) locoregional discrimination of the sequential infiltration of distinct immune cell populations together with in-depths characterization of tissue properties and (ii) to monitor the effect of MI on immune cell recruitment to other major target organs. In the long run, this approach might also be transferred to the clinical setting for identification of individual inflammation patterns in patients to tailor adequate therapy regimes for precision medicine.

19F MRI已被证明是一种极好的无背景炎症成像工具。为此，注射乳化的全氟碳化合物（pfc），它们优先被循环单核细胞吞噬，浸润到炎症灶后，可通过1H/19F MRI检测到单核细胞。然而，在一定条件下，b细胞、树突状细胞或中性粒细胞也可内化PFCs，小尺寸的PFCs可通过渗漏的内皮被动扩散到炎性病变。因此，检测到的19F信号来自于血液中被标记和/或局部内化pfc的细胞的复杂混合物。最近，我们通过将配体装备的pfc定向到特定的表位，从而促进了19F MRI方法的发展，从而能够主动靶向单个细胞群。此外，我们开发了一种成像技术，用于同时检测具有不同光谱特征的不同PFCs，从而同时可视化多个目标。为了克服所描述的局限性，本提案旨在扩展当前的方法：1)特异性靶向中性粒细胞，经典/非经典单核细胞和CD4+ t细胞：为此，我们将生成pfc来特异性标记血液中的不同细胞类型，并实施“多色”19F压缩传感技术以提高检测阈值。我们已经发现了一种针对中性粒细胞的靶向肽，并将利用噬菌体展示筛选来识别针对这两种单核细胞亚群的新型配体。CD4+ t细胞将被抗CD4单抗/单抗衍生物和/或具有CD4+ t细胞特异性PFC内化特性的新型转基因小鼠靶向。2)追踪心肌梗死后免疫细胞的顺序浸润和组织结构的改变：监测心肌梗死后中性粒细胞、经典/非经典单核细胞和CD4+ t细胞进入心脏的浸润情况，将能够精确绘制当前炎症状态的质量。结合多参数1H MRI (T1, T2， CEST)，可以全面表征局部炎症和组织结构的相关改变。为了解决器官间的串扰，骨髓、脾脏、肾脏和肺也被纳入成像方案，这将提供心肌梗死后整体免疫细胞运输的见解。通过这种方法，我们将进一步研究改变的免疫易感如何影响心肌梗死后的结果。这种方法将允许(i)对不同免疫细胞群的顺序浸润进行局部区域区分，并深入表征组织特性；（ii）监测心肌梗死对免疫细胞向其他主要靶器官募集的影响。从长远来看，这种方法也可能被转移到临床环境中，以识别患者的个体炎症模式，为精准医疗量身定制适当的治疗方案。