Lymph node (LN)‐resident dendritic cells (DCs) are a promising target for vaccination given their professional antigen‐presenting capabilities and proximity to a high concentration of immune cells. Direct intra‐LN injection has been shown to greatly enhance the immune response to vaccine antigens compared to traditional intramuscular injection, but it is infeasible to implement clinically in a vaccination campaign context. Employing the passive lymphatic flow of antigens to target LNs has been shown to increase total antigen uptake by DCs more than inflammatory adjuvants, which recruit peripheral DCs. Herein, we describe a novel vaccination platform in which two complementary multi‐arm poly(ethylene glycol) (PEG) polymers—one covalently bound to the model antigen ovalbumin (OVA)—are injected subcutaneously into two distinct sites. These materials then drain to the same LN through different lymphatic vessels and, upon meeting in the LN, rapidly crosslink. This system improves OVA delivery to, and residence time within, the draining LN compared to all control groups. The crosslinking of the two PEG components also improves humoral immunity without the need for any pathogen‐mimicking adjuvants. Further, we observed a significant increase in non‐B/T lymphocytes in LNs cross‐presenting the OVA peptide SIINFEKL on MHC I over a dose‐matched control containing alum, the most common clinical adjuvant, as well as an increase in DC activation in the LN. These data suggest that this platform can be used to deliver antigens to LN‐resident immune cells to produce a stronger humoral and cellular immune response over materials‐matched controls without the use of traditional adjuvants.

中文翻译：

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携带抗原聚合物的淋巴结内交联可增强体液免疫和树突状细胞活化


淋巴结 （LN） 驻留的树突状细胞 （DC） 是一个很有前途的疫苗接种目标，因为它们具有专业的抗原呈递能力和接近高浓度的免疫细胞。与传统的肌肉注射相比，直接 LN 内注射已被证明可以大大增强对疫苗抗原的免疫反应，但在疫苗接种运动背景下临床实施是不可行的。利用抗原的被动淋巴流靶向 LN 已被证明比募集外周 DC 的炎性佐剂更能增加 DC 对总抗原的摄取。在这里，我们描述了一种新的疫苗接种平台，其中两种互补的多臂聚乙二醇 （PEG） 聚合物——一种与模型抗原卵清蛋白 （OVA） 共价结合——皮下注射到两个不同的部位。然后，这些物质通过不同的淋巴管排流到同一个 LN，并在 LN 中相遇时迅速交联。与所有对照组相比，该系统改善了 OVA 向引流 LN 的递送和在引流 LN 内的停留时间。两种 PEG 成分的交联还提高了体液免疫力，而无需任何模拟病原体的佐剂。此外，我们观察到在含有明矾（最常见的临床佐剂）的剂量匹配对照上，在 MHC I 上交叉呈递 OVA 肽 SIINFEKL 的 LNs 中非 B/T 淋巴细胞显着增加，并且 LN 中 DC 激活的增加。这些数据表明，该平台可用于将抗原递送至 LN 驻留免疫细胞，与材料匹配的对照相比，无需使用传统佐剂即可产生更强的体液和细胞免疫反应。