Immunotherapy for Peanut Allergy

描述（由申请人提供）：花生过敏是对食物的最严重的速发型超敏反应之一，就反应的持续性和严重性而言，它似乎是一个日益严重的问题。对花生过敏原的偏向性Th2/IgE免疫反应对于超敏反应至关重要。导致口服耐受性缺乏和Th2/IgE对花生过敏原产生偏倚的机制仍不明确，阻碍了预防花生和其他食物过敏的新的有效方法的开发。了解花生过敏的分子机制对于确保花生过敏患者的最终成功治疗至关重要。遗传和环境因素都是过敏的原因。环境因素对食物过敏尤其重要，因为胃肠道中同时存在植物植物群和食物过敏原。微生物和食物过敏原与先天免疫系统之间的相互作用可能决定了对过敏原的适应性反应。Toll样受体（TLR）是微生物识别的主要受体。TLR信号通过调节抗原呈递细胞（APC）的抗原呈递和细胞因子产生来控制适应性免疫应答。在小鼠中，TLR4缺乏可导致对花生过敏。此外，我们的初步数据显示，细胞信号分子甘油二酯（DAG）激酶？(DGK?),其通过磷酸化将DAG转化为磷脂酸（PA），正调节TLR诱导的IL-12产生。缺乏DGK？对花生过敏原有明显的超敏反应。我们假设TLR诱导的先天免疫应答促进对花生过敏原的口服耐受，并且在花生过敏原挑战时诱导TLR介导的先天免疫可能有效地降低花生过敏原性。本研究旨在建立一种新的花生过敏小鼠模型，提高我们对先天免疫系统和适应性免疫系统在口服耐受发展中的关系的理解，并开发一种新的花生过敏患者的免疫治疗方法。这项拨款申请旨在研究花生过敏症发展中的机制。这些研究有望通过建立一种新的花生过敏小鼠模型来确定先天免疫应答在花生过敏发病机制中的作用，并通过靶向Toll样受体来提供新的花生过敏治疗试剂。

DESCRIPTION (provided by applicant): Peanut allergy is one of the most serious of the immediate hypersensitivity reactions to foods in terms of persistence and severity of reaction, and it appears to be a growing problem. A biased Th2/IgE immune reaction to peanut allergens is critical for the hypersensitivity response. The mechanisms leading to a lack of oral tolerance and generation of Th2/IgE bias to peanut allergens have remained undefined, hindering the development of new and effective approaches to prevent peanut as well as other food allergies. An understanding of the molecular mechanisms of peanut allergy is vital to ensure the eventual successful treatment of peanut allergic patients. Both genetic and environmental factors contribute to allergies. Environmental factors can be particularly important for food allergy because of the co-presence of commensal flora and food allergens in the gastrointestinal tract. The interplay between microbials and food allergens with the innate immune system may dictate the adaptive responses to allergens. Toll-like receptors (TLRs) are the major receptors for microbial recognition. TLR signals control adaptive immune responses by regulating antigen presentation and cytokine production by antigen presenting cells (APCs). In mice, deficiency of TLR4 can lead to hypersensitivity to peanuts. Furthermore, our preliminary data revealed that the cell signaling molecule diacylglycerol (DAG) kinase? (DGK?), which converts DAG to phosphatidic acid (PA) through phosphorylation, positively regulates TLR-induced IL-12 production. Deficiency of DGK? in mice causes significant hypersensitivity reactions to peanut allergens. We hypothesize that TLR-induced innate immune responses promote oral tolerance to peanut allergens and that inducing TLR-mediated innate immunity at the time of peanut allergen challenge may effectively decrease peanut allergenicity. Studies in this proposal are designed to establish a new murine model for peanut allergy, improve our understanding of the relationship between the innate and adaptive immune system in the development of oral tolerance, and develop a novel immunotherapy for treating peanut allergy patients. This grant application aims to investigate the mechanisms that are involved in the development of peanut allergy. The proposed studies are expected to determine the role of innate immune responses in the pathogenesis of peanut allergy by using a new murine model for the disease and also to provide new therapeutic reagents for peanut allergy by targeting the Toll-like receptors.