In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles
In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles
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DOI：
10.1073/pnas.1105200108
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发表时间：
2011-09-20
影响因子：
11.1
通讯作者：
Irvine, Darrell J.
中科院分区：
文献类型：
--
作者：
Jewell, Christopher M.;Lopez, Sandra C. Bustamante;Irvine, Darrell J.
最近的研究已经证明了一种简单的、潜在的通用策略，即通过淋巴结内注射来增强疫苗效力。迄今为止，结内免疫研究的重点是提供无佐剂疫苗（例如，裸DNA、肽或蛋白质）。我们假设，将i - ln疫苗与允许分子佐剂持续剂量到局部组织微环境的控释生物材料相结合，将进一步增强这种有希望的疫苗接种策略。为了验证这一想法，我们将toll样受体-3配体聚肌苷酸（polyIC）封装在可生物降解的聚（丙交酯-羟基乙酸）微粒（MPs）中，这些微粒被设计成留在细胞外并在LN中释放polyIC数天。与相同剂量的可溶性polyIC或纳米颗粒配制的polyIC相比，结内注射MPs增加了LNs中polyIC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和更持久的树突状细胞活化。单次注射后，淋巴节点内注射卵清蛋白与释放polyIC的MPs混合，增强了体液反应，并将卵清蛋白特异性T细胞在所有CD8（+）细胞中的频率扩大到18%（比im给予相同疫苗高8.2倍），这种反应不能与负载polyIC的纳米颗粒混合的抗原或10倍大剂量的可溶性polyIC相匹配。因此，使用缓释佐剂进行免疫接种可能是一种广泛适用的策略，以增强治疗性或预防性疫苗。
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(inosiniccytidylic 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.