Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles
Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles
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DOI：
10.1111/j.1365-2567.2005.02268.x
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发表时间：
2006-01-01
期刊：
影响因子：
6.4
通讯作者：
Hanlon, DJ
中科院分区：
文献类型：
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作者：
Shen, H;Ackerman, AL;Hanlon, DJ
CD 8（+）T细胞反应在肿瘤和传染病的免疫控制中至关重要。为了使CD 8（+）T细胞针对这些细胞相关抗原进行初始化，外源性抗原必须由专职抗原呈递细胞（APC）交叉呈递。虽然树突状细胞对可溶性抗原的交叉呈递在体内是可检测的，但效率低，限制了基于蛋白质的疫苗接种的临床效用。为了提高呈递效率，我们从可生物降解的聚合物聚（D，L-丙交酯-共-乙交酯）（PLGA）中产生纳米颗粒，以将抗原递送到主要组织相容性复合物（MHC）I类抗原呈递途径中。在原代小鼠骨髓来源的树突状细胞（BMDCs）中，PLGA封装的卵清蛋白（OVA）的MHC I类呈递刺激T细胞白细胞介素-2分泌，其浓度比可溶性抗原低1000倍，比抗原包被的乳胶珠低10倍。这些微粒还充当细胞内抗原储存库，导致OVA持续呈现MHC I类72小时，96小时后仅减少20%，此时可溶性和乳胶珠相关抗原的呈现无法检测到。胞质溶胶提取表明，通过PLGA颗粒的抗原递送增加了从内体逃逸到细胞质中的蛋白质的量，从而增加了外源性抗原对经典的MHC I类加载途径的接近。这些数据表明，PLGA颗粒介导的抗原递送的独特性质显著增强和维持由MHC I类的外源性抗原呈递，潜在地促进这些颗粒在疫苗接种中的临床使用。
CD8(+) T-cell responses are critical in the immunological control of tumours and infectious diseases. To prime CD8(+) T cells against these cell-associated antigens, exogenous antigens must be cross-presented by professional antigen-presenting cells (APCs). While cross-presentation of soluble antigens by dendritic cells is detectable in vivo, the efficiency is low, limiting the clinical utility of protein-based vaccinations. To enhance the efficiency of presentation, we generated nanoparticles from a biodegradable polymer, poly(D,L-lactide-co-glycolide) (PLGA), to deliver antigen into the major histocompatibility complex (MHC) class I antigen presentation pathway. In primary mouse bone marrow-derived dendritic cells (BMDCs), the MHC class I presentation of PLGA-encapsulated ovalbumin (OVA) stimulated T cell interleukin-2 secretion at 1000-fold lower concentration than soluble antigen and 10-fold lower than antigen-coated latex beads. The microparticles also served as an intracellular antigen reservoir, leading to sustained MHC class I presentation of OVA for 72 hr, decreasing by only 20% after 96 hr, a time at which the presentation of soluble and latex bead-associated antigens was undetectable. Cytosol extraction demonstrated that antigen delivery via PLGA particles increased the amount of protein that escaped from endosomes into the cytoplasm, thereby increasing the access of exogenous antigen to the classic MHC class I loading pathway. These data indicate that the unique properties of PLGA particle-mediated antigen delivery dramatically enhance and sustain exogenous antigen presentation by MHC class I, potentially facilitating the clinical use of these particles in vaccination.