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Synergistic effects of dendritic cell targeting and laser-microporation on enhancing epicutaneous skin vaccination efficacy
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2017-09-14 , DOI: 10.1016/j.jconrel.2017.09.020
Yoan Machado , Sanne Duinkerken , Veronika Hoepflinger , Melissa Mayr , Evgeniia Korotchenko , Almedina Kurtaj , Isabel Pablos , Markus Steiner , Angelika Stoecklinger , Joyce Lübbers , Maximillian Schmid , Uwe Ritter , Sandra Scheiblhofer , Michael Ablinger , Verena Wally , Sarah Hochmann , Anna M. Raninger , Dirk Strunk , Yvette van Kooyk , Josef Thalhamer , Richard Weiss

Due to its unique immunological properties, the skin is an attractive target tissue for allergen-specific immunotherapy. In our current work, we combined a dendritic cell targeting approach with epicutaneous immunization using an ablative fractional laser to generate defined micropores in the upper layers of the skin. By coupling the major birch pollen allergen Bet v 1 to mannan from S. cerevisiae via mild periodate oxidation we generated hypoallergenic Bet-mannan neoglycoconjugates, which efficiently targeted CD14+ dendritic cells and Langerhans cells in human skin explants. Mannan conjugation resulted in sustained release from the skin and retention in secondary lymphoid organs, whereas unconjugated antigen showed fast renal clearance. In a mouse model, Bet-mannan neoglycoconjugates applied via laser-microporated skin synergistically elicited potent humoral and cellular immune responses, superior to intradermal injection. The induced antibody responses displayed IgE-blocking capacity, highlighting the therapeutic potential of the approach. Moreover, application via micropores, but not by intradermal injection, resulted in a mixed TH1/TH17-biased immune response. Our data clearly show that applying mannan-neoglycoconjugates to an organ rich in dendritic cells using laser-microporation is superior to intradermal injection. Due to their low IgE binding capacity and biodegradability, mannan neoglycoconjugates therefore represent an attractive formulation for allergen-specific epicutaneous immunotherapy.



中文翻译:

树突状细胞靶向和激光微穿孔对增强表皮皮肤疫苗接种效果的协同作用

由于其独特的免疫学特性,皮肤是变应原特异性免疫疗法的诱人靶组织。在我们目前的工作中,我们将树突状细胞靶向方法与使用烧蚀性分级激光的表皮免疫相结合,以在皮肤的上层中产生明确的微孔。通过温和的高碘酸氧化将主要的桦树花粉变应原Bet v 1与啤酒酵母中的甘露聚糖偶联,我们生成了低变应原性的Bet-甘露聚糖新糖缀合物,可有效靶向CD14 +人皮肤外植体中的树突状细胞和朗格汉斯细胞。甘露聚糖偶联导致皮肤持续释放并保留在次级淋巴器官中,而未偶联的抗原则显示出快速的肾脏清除率。在小鼠模型中,通过激光微孔皮肤施加的Bet-甘露聚糖新糖缀合物可协同产生强效的体液和细胞免疫应答,优于皮内注射。诱导的抗体反应显示出IgE阻断能力,突出了该方法的治疗潜力。此外,通过微孔而不是通过皮内注射的应用导致混合的偏向于TH1 / TH17的免疫应答。我们的数据清楚地表明,使用激光微穿孔技术将甘露聚糖-新糖缀合物应用于富含树突状细胞的器官要优于皮内注射。

更新日期:2017-09-14
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