Parakkattel Dixy, Ruprecht Nico, Broekmann Peter, Guimbal Sarah, Stüdle Chiara, Soldati Sasha, Heverhagen Johannes T, Engelhardt Britta, von Tengg-Kobligk Hendrik
Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, University of Bern, Bern, Switzerland.
Department of BioMedical Research, University of Bern, Bern, Switzerland.
Fluids Barriers CNS. 2025 Jul 29;22(1):80. doi: 10.1186/s12987-025-00674-5.
Gadolinium (Gd) deposition in the brain was observed in patients with history of gadolinium-based contrast agent (GBCA) administration. However, the exact mechanism behind this deposition remains unclear, especially given that an intact blood-brain barrier (BBB) is considered impermeable to GBCA. In this study, we propose that immune cells might play a role in facilitating GBCA entry into the brain despite an intact BBB.
Gadoterate meglumine, gadoteridol, gadobutrol and gadodiamide were investigated as GBCAs. Immune cells from human donor buffy coats were isolated, incubated with the GBCA and used in the experiments. Gd associated with the immune cells were measured using single-cell inductively coupled mass spectrometry (SC-ICP-MS). Flow cytometry analysis was performed to characterise the adhesion molecule expression profile on the immune cells and binding assay was employed to check the binding of Gd treated immune cells with endothelial ligands in static conditions. An in vitro model of the human BBB that prevents free diffusion of GBCA across was further used to observe immune cell behaviour at the BBB under physiological flow, in vitro.
Our findings confirm that various immune cells, including CD4 T cells, CD8 T cells, monocytes, NK cells and B cells are capable of taking up the different GBCAs. Furthermore, we demonstrate that GBCA loading does not impair immune cell interaction with the endothelial ligands required for successful extravasation across the BBB under static conditions. Most importantly, we show that T cells and monocytes, loaded with the different contrast agents, extravasated across an in vitro BBB model under physiological flow conditions in a comparable manner to non GBCA loaded cells.
Taken together, our in vitro observations show that immune cells can transport GBCA across the BBB and could lead to permanent deposition of Gd in the brain.
在接受过钆基造影剂（GBCA）注射的患者中观察到钆（Gd）在大脑中的沉积。然而，这种沉积背后的确切机制仍不清楚，特别是考虑到完整的血脑屏障（BBB）被认为对GBCA是不可渗透的。在本研究中，我们提出尽管血脑屏障完整，但免疫细胞可能在促进GBCA进入大脑中发挥作用。
研究了钆特酸葡甲胺、钆特醇、钆布醇和钆双胺作为GBCA。从人类供体血沉棕黄层中分离免疫细胞，与GBCA一起孵育并用于实验。使用单细胞电感耦合质谱（SC-ICP-MS）测量与免疫细胞相关的Gd。进行流式细胞术分析以表征免疫细胞上的粘附分子表达谱，并采用结合试验检查经Gd处理的免疫细胞与静态条件下内皮配体的结合。进一步使用一种可防止GBCA自由扩散的人血脑屏障体外模型，以观察体外生理流动状态下血脑屏障处的免疫细胞行为。
我们的研究结果证实，包括CD4 T细胞、CD8 T细胞、单核细胞、NK细胞和B细胞在内的各种免疫细胞都能够摄取不同的GBCA。此外，我们证明在静态条件下，GBCA负载不会损害免疫细胞与成功穿越血脑屏障所需的内皮配体的相互作用。最重要的是，我们表明负载不同造影剂的T细胞和单核细胞在生理流动条件下以与未负载GBCA的细胞相当的方式穿越体外血脑屏障模型。
综上所述，我们的体外观察结果表明免疫细胞可以将GBCA转运穿过血脑屏障，并可能导致Gd在大脑中永久沉积。
