Immunotherapy for Peanut Allergy

描述(申请人提供)：花生过敏是对食物的即刻过敏反应中最严重的反应之一，就反应的持久性和严重性而言，它似乎是一个日益严重的问题。针对花生变应原的偏向Th2/IgE免疫反应是超敏反应的关键。导致对花生过敏原缺乏口服耐受性和产生Th2/IgE偏向的机制尚不清楚，阻碍了预防花生和其他食物过敏的新的有效方法的发展。了解花生过敏的分子机制对于确保花生过敏患者的最终治疗是至关重要的。遗传和环境因素都会导致过敏。环境因素对食物过敏可能特别重要，因为胃肠道中存在共生菌群和食物过敏原。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样受体是微生物识别的主要受体。TLR信号通过调节抗原提呈细胞(APC)的抗原提呈和细胞因子的产生来控制适应性免疫反应。在小鼠中，TLR4缺乏会导致对花生的过敏。此外，我们的初步数据显示，细胞信号分子二酰甘油(DAG)激酶？(DGK？)通过磷酸化将DAG转化为磷脂酸(PA)，正向调节TLR诱导的IL-12的产生。DGK缺乏？可引起小鼠对花生过敏原的显著过敏反应。我们假设TLR诱导的先天免疫反应促进了对花生变应原的口服耐受性，在花生变应原攻击时诱导TLR介导的先天免疫可能有效地降低花生的过敏性。本研究旨在建立一种新的花生过敏小鼠模型，加深对先天免疫系统和获得性免疫系统在口服耐受形成过程中关系的认识，并开发一种治疗花生过敏患者的新型免疫疗法。这项拨款申请旨在调查花生过敏的发生机制。这项拟议的研究有望通过一种新的花生过敏小鼠模型来确定先天免疫反应在花生过敏发病机制中的作用，并通过靶向Toll样受体来提供治疗花生过敏的新试剂。

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.