Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15745-50. doi: 10.1073/pnas.1105200108. Epub 2011 Sep 6.
Recent studies have demonstrated a simple, potentially universal strategy to enhance vaccine potency, via intralymph node (i.LN) injection. To date, intranodal immunization studies have focused on the delivery of unadjuvanted vaccines (e.g., naked DNA, peptide, or protein). We hypothesized that combining i.LN vaccination with controlled release biomaterials permitting sustained dosing of molecular adjuvants to the local tissue microenvironment would further enhance this promising vaccination strategy. To test this idea, we encapsulated the Toll-like receptor-3 ligand poly(inosinic:cytidylic acid) (polyIC) in biodegradable poly(lactide-co-glycolide) microparticles (MPs) designed to remain extracellular and release polyIC in the LN over several days. Intranodal injection of MPs increased persistence of polyIC in LNs compared to the same dose of soluble polyIC or polyIC formulated in nanoparticles, leading to increased accumulation of Toll-like receptor agonist in LN-resident antigen presenting cells and more enduring dendritic cell activation. Intralymph node injection of ovalbumin mixed with polyIC-releasing MPs enhanced the humoral response and expanded ovalbumin-specific T cells to frequencies as high as 18% among all CD8(+) cells following a single injection (8.2-fold greater than the same vaccine given i.m.), a response that could not be matched by antigen mixed with polyIC-loaded nanoparticles or a 10-fold greater dose of soluble polyIC. Thus, i.LN immunization with slow release-formulated adjuvants may be a broadly applicable strategy to enhance therapeutic or prophylactic vaccines.
最近的研究表明，通过淋巴结内（i.LN）注射，有一种简单、具有潜在普遍性的增强疫苗效力的策略。迄今为止，淋巴结内免疫接种的研究主要集中在未加 adjuvant 的疫苗（例如裸露 DNA、肽或蛋白质）的传递上。我们假设，将 i.LN 疫苗接种与控制释放生物材料相结合，允许分子 adjuvant 持续向局部组织微环境给药，将进一步增强这一有前途的疫苗接种策略。为了验证这一想法，我们将 Toll 样受体 3 配体聚（inosinic：cytidylic acid）（polyIC）包封在可生物降解的聚（乳酸-共-乙醇酸）微球（MPs）中，设计成在 LN 中保持细胞外并在数天内释放 polyIC。与相同剂量的可溶性 polyIC 或纳米颗粒中的 polyIC 制剂相比，淋巴结内注射 MPs 增加了 polyIC 在 LN 中的持久性，导致 LN 驻留抗原呈递细胞中 Toll 样受体激动剂的积累增加，树突状细胞的激活更持久。与释放 polyIC 的 MPs 混合的卵清蛋白的淋巴结内注射增强了体液反应，并将卵清蛋白特异性 T 细胞扩增至所有 CD8（+）细胞中的频率高达 18%，单次注射（比相同疫苗肌内注射高 8 倍），这种反应不能通过与负载 polyIC 的纳米颗粒混合的抗原或 10 倍更大剂量的可溶性 polyIC 匹配。因此，淋巴结内免疫接种用缓释配方的 adjuvant 可能是增强治疗性或预防性疫苗的一种广泛适用的策略。
