Toll-like receptor 5 ligand based vaccines for prophylactic and therapeutic intervention of IgE-mediated allergies

虽然使用变应原粗提物的变应原特异性免疫疗法(SIT)已被确定用于某些吸入性过敏，但只有少数患者接受SIT。SIT仍然存在严重不良副作用的风险，目前还不能用于食物过敏的治疗。为了提高效力、安全性和依从性，需要新的疫苗接种策略。预防IgE介导的过敏反应的新方法将结合重组变应原和佐剂，例如通过病原体相关分子模式促进的免疫调节。该项目将探索由TLR5配体鞭毛蛋白FlaA和过敏原组成的重组融合蛋白是否可能成为食物过敏的有效候选疫苗。与FlaA和过敏原的混合物相比，FlaA-过敏原融合蛋白的免疫调节特性将在体外和体内使用野生型和敲除小鼠进行评估。在体外，使用分化的骨髓来源的树突状细胞(BMDC)并与过敏原特异性的CD4+T细胞共培养，将致力于阐明免疫调节的机制。预防性和治疗性疫苗接种将在适当的小鼠模型中根据症状以及对先天性和获得性免疫反应的调节进行评估。这项拟议的研究将提供关于潜在的基于TLR5配体的疫苗用于干预过敏的安全性和有效性的信息。

Although allergen-specific immunotherapy (SIT) using crude allergen extracts is established for certain inhalant allergies, only few patients undergo SIT. SIT still possess the risk of severe unwanted side effects and is currently not available for the treatment of food allergies. In order to increase efficacy, safety and compliance, novel vaccination strategies are required. Novel approaches for the prevention of IgE-mediated allergies will combine recombinant allergens and adjuvants, e.g. immune modulation facilitated by pathogen-associated molecular patterns. The project will explore whether recombinant fusion proteins, consisting of TLR5-ligand flagellin flaA and allergens, may be effective vaccine candidates for food allergies. Immune modulating properties of the flaA-allergen fusion proteins, in comparison to the mixture of flaA and allergen, will be evaluated in vitro and in vivo using wild-type and knock-out mice. In vitro studies using differentiated bone marrow derived dendritic cells (BMDC) and co-cultured with allergen specific CD4+ T cells will be addressed to elucidate the mechanism of the immune modulation. Prophylactic and therapeutic vaccination will be evaluated in appropriate mice models in regard to symptoms, and the modulation of the innate and adaptive immune responses. The proposed study will provide information regarding the safety and efficacy of potential TLR5-ligand based vaccines for the intervention of allergies.