Intrinsic Adjuvanticity of Branched Polyethylenemine In Vitro and Subcutaneously
Intrinsic Adjuvanticity of Branched Polyethylenemine In Vitro and Subcutaneously
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支化聚乙烯胺体外和皮下的内在佐剂作用
DOI：
10.1021/acsapm.9b01016
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发表时间：
2020
影响因子：
5
通讯作者：
Juan Tao
中科院分区：
文献类型：
--
作者：
Chen Shen;Yujie Gao;Jun Li;Hongyao Du;Ruijing Liang;Yanhong Sun;Jun Xie;Liyun Dong;Yamin Zhang;Jinjin Zhu;Bo Zhang;Guanxin Shen;Xiang Chen;Jintao Zhu;Juan Tao
支化聚乙烯亚胺（BPEI）是一种阳离子聚合物，已被用作疫苗中的抗原载体。然而，其内在的佐剂性和潜在的机制仍不清楚。本文系统地探讨了一系列BPEI对体外培养的骨髓来源树突状细胞（BMDCs）的直接刺激作用。只有高浓度的分子量（MW）等于或大于25 kDa的BPEI显示出免疫激活作用，表明MW和阳离子度都有助于这种作用。在电荷中和实验中，BPEI的内在佐剂性也表现出阳离子度依赖性模式。此外，我们确定活性氧（ROS）作为BPEI介导的BMDC激活的关键信使。然而，高分子量和阳离子电荷的BPEI对树突状细胞产生直接的毒性，这将限制其在体内的应用。因此，我们引入成纤维细胞作为旁观者细胞，发现BPEI处理的成纤维细胞将刺激作用传递给BMDCs，但细胞毒性检测不到。在皮下刺激期间，对应于成纤维细胞介导的共培养系统，BPEI诱导炎症微环境和局部免疫细胞浸润，而没有明显的细胞死亡。据我们所知，这是第一次系统和深刻的调查BPEI的内在佐剂性和功能的探索存在的旁观者细胞。这一发现为推进基于BPEI的疫苗铺平了道路，并将深入了解具有类似特性的其他免疫活性生物材料的使用。
Branched polyethylenimine (BPEI) is a cationic polymer and has been applied as an antigen carrier in vaccines. However, its intrinsic adjuvanticity and underlying mechanism remain unclear. Here, we systematically explored the direct stimulation effects of a series of BPEI on bone-marrow-derived dendritic cells (BMDCs)in vitro. Only high concentrations of BPEI with molecular weight (MW) equal to or greater than 25 kDa showed an immune-activating effect, indicating that bothMWand cationic degree contribute to this effect. In a charge neutralization experiment, the intrinsic adjuvanticity of BPEI also demonstrated a cationic degree-dependent pattern. Moreover, we identified reactive oxygen species (ROS) as the crucial messengers in BPEI-mediated BMDC activation. However, highMWand cationic charges from the BPEI exerted a direct toxicity on dendritic cells, which would restrict itsin vivoapplications. Therefore, we introduced fibroblasts as bystander cells and found that BPEI-treated fibroblasts passed stimulation effects to BMDCs with undetectable cytotoxicity. During subcutaneous stimulation, which corresponded to the fibroblast-mediated coculture system, BPEI induced an inflammatory microenvironment and local immune cell infiltration without obvious cell death. To the best of our knowledge, this is the first systematic and incisive investigation of BPEI’s intrinsic adjuvanticity and its functional exploration in the presence of bystander cells. This finding paves the way to advance the BPEI-based vaccines and will give insights into the use of other immunoactive biomaterials with similar properties.