Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
Adv Healthc Mater. 2021 Aug;10(15):e2001899. doi: 10.1002/adhm.202001899. Epub 2021 Apr 30.
Vaccines are commonly administered subcutaneously or intramuscularly, and local immune cells, notably dendritic cells (DCs), play a significant role in transporting vaccine antigens and adjuvants to draining lymph nodes. Here, it is compared how soluble and biomaterial-mediated delivery of Toll-like receptor (TLR)-targeted adjuvants, monophosphoryl lipid A (MPLA, TLR4 ligand) and 5'-C-phosphate-G-3' DNA (CpG DNA, TLR9 ligand), modulate 3D chemotaxis of bone marrow-derived dendritic cells (BMDCs) toward lymphatic chemokine gradients. Within microfluidic devices containing 3D collagen-based matrices to mimic tissue conditions, soluble MPLA increases BMDC chemotaxis toward gradients of CCL19 and CCL21, while soluble CpG has no effect. Delivering CpG on poly(lactic-co-glycolic) acid microparticles (MPs) enhances BMDC chemotaxis compared to MPLA-encapsulated MPs, and when co-delivered, MPLA and CpG do not synergistically enhance BMDC migration. It is concluded that supplementing granulocyte-macrophage colony stimulating factor-derived BMDC culture with interleukin-4 is necessary to induce CCR7 expression and chemotaxis of BMDCs. Different cell subsets in BMDC culture upregulate CCR7 in response to soluble versus biomaterial-loaded MPLA and CpG, and CCR7 expression does not consistently correlate with functional migration. The results show both adjuvant type and delivery method influence chemotaxis of DCs, and these findings uncover new directions for the rational design of vaccine formulations.
疫苗通常通过皮下或肌肉内给药，局部免疫细胞，特别是树突状细胞（DC），在将疫苗抗原和佐剂运送到引流淋巴结方面发挥着重要作用。在这里，比较了可溶性和生物材料介导的 Toll 样受体（TLR）靶向佐剂，单磷酰脂质 A（MPLA，TLR4 配体）和 5'-C-磷酸-G-3' DNA（CpG DNA，TLR9 配体）的递送方式如何调节骨髓来源的树突状细胞（BMDC）向淋巴趋化因子梯度的 3D 趋化性。在包含 3D 胶原基质的微流控装置中，以模拟组织条件，可溶性 MPLA 增加了 BMDC 向 CCL19 和 CCL21 梯度的趋化性，而可溶性 CpG 则没有影响。与封装 MPLA 的 MPs 相比，在聚（乳酸-共-乙醇酸）酸微球（MPs）上递送 CpG 增强了 BMDC 的趋化性，并且当共同递送时，MPLA 和 CpG 不会协同增强 BMDC 的迁移。研究结论是，在用粒细胞-巨噬细胞集落刺激因子衍生的 BMDC 培养物补充白细胞介素-4 是诱导 BMDC 表达 CCR7 和趋化性所必需的。BMDC 培养物中的不同细胞亚群对可溶性或生物材料负载的 MPLA 和 CpG 做出反应，上调 CCR7，而 CCR7 的表达并不始终与功能迁移相关。结果表明，佐剂类型和递送方法都会影响 DC 的趋化性，这些发现为疫苗配方的合理设计开辟了新的方向。
