Peanut Glycolipid Antigens Activate Natural Killer T Cells Causing Severe Allergy

花生糖脂抗原激活自然杀伤 T 细胞，导致严重过敏

基本信息

批准号：
7877661
负责人：
DALE T UMETSU
金额：
$ 24.97万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7877661
关键词：
Adjuvant Age Allergens Allergic Allergy to peanuts Anaphylaxis Antigen-Presenting Cells Antigens Asthma Autoimmunity Biological Models Bone Marrow Carbohydrates Cell Line Chronic Obstructive Airway Disease Chronic lung disease Communicable Diseases Complex Data Dendritic Cells Development Disease Endotoxins Failure Flour Food Food Hypersensitivity Glycolipids Goals High Prevalence Human Hypersensitivity IgE IgG1 Immune Immune response In Vitro Individual Inflammation Inflammatory Intestinal Mucosa Laboratories Lead Lipids Lung Malignant Neoplasms Memory Microbe Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Normal Cell Ovalbumin Pathogenesis Pathway interactions Patients Peanuts - dietary Plants Play Production Property Proteins Reagent Research Respiratory System Respiratory tract structure Role Sphingomonas Spleen Structure System T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte Subsets Th2 Cells Time Work adaptive immunity airway hyperresponsiveness airway inflammation cell type cytokine experience in vivo killer T cell microorganism mucosal site novel peripheral blood respiratory response

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this project is to better define peanut allergens, and to identify the properties of peanuts that result in the high prevalence of peanut sensitization, the failure of peanut allergy to resolve over time, and explain the disproportionate number of severe episodes of peanut induced anaphylaxis. We hypothesize that peanuts contain lipid and lipid-carbohydrate complexes that activate innate immune mechanisms, providing adjuvant effects, which greatly enhance peanut specific adaptive immune responses. We will examine lipid complexes from peanuts, and their capacity to activate natural killer T (NKT) cells, which are known to respond to glycolipids and to contribute significantly to adaptive immunity and to inflammatory diseases such as infectious diseases, autoimmunity, cancer and asthma. We have previously shown that NKT cells at mucosal sites play a critical role in the development of airway inflammation and asthma. In addition, we have shown that glycolipids from the bacterial species Sphingomonas can directly activate pulmonary NKT cells and induce airway inflammation and airway hyper-reactivity, a cardinal feature of asthma. These results suggest that NKT cells in mucosal tissues may respond to agents such as microbes and plant products containing glycolipids, and that NKT cells could play a previously unsuspected but critical role in regulating many immune responses in mucosal tissues to environmental glycolipids. Although only a few glycolipids are currently known to activate NKT cells, we believe that some foods, such as peanuts, may contain glycolipids that can stimulate NKT cells, resulting in the activation of innate and adaptive mucosal immune responses. We therefore propose to purify and identify glycolipids from peanuts that can directly activate NKT cells. We believe that peanut glycolipids can activate NKT cells, thereby activating innate immune mechanisms that then greatly enhance adaptive immunity to peanuts. We will study murine systems, as well as human cells from normal and peanut allergic individuals, examining both in vitro and in vivo responses. We are working with an outstanding lipid biochemist, and have extensive experience working with human and murine NKT cells. Moreover, we already have exciting preliminary data demonstrating that purified peanut glycolipids can indeed activate NKT cells, suggesting that our hypothesis is correct, and that our studies are feasible and likely to generate important new information. We believe that our studies are likely to greatly expand the fundamental understanding of the types of immune responses that occur at mucosal sites, and how foods, such as peanuts, can induce immune responses that result in food allergy.

描述（由申请人提供）：该项目的长期目标是更好地定义花生过敏原，并确定花生的特性，这些特性导致花生过敏的高流行、花生过敏未能随着时间的推移而解决，并解释严重事件的不成比例的数量花生引起的过敏反应。我们假设花生含有脂质和脂质-碳水化合物复合物，可以激活先天免疫机制，提供佐剂作用，从而大大增强花生特异性适应性免疫反应。我们将研究花生中的脂质复合物及其激活自然杀伤 T (NKT) 细胞的能力，众所周知，自然杀伤 T 细胞会对糖脂产生反应，并对适应性免疫和传染病、自身免疫、癌症和哮喘等炎症性疾病做出重大贡献。我们之前已经证明，粘膜部位的 NKT 细胞在气道炎症和哮喘的发展中发挥着关键作用。此外，我们还发现，鞘氨醇单胞菌中的糖脂可以直接激活肺部 NKT 细胞，诱发气道炎症和气道高反应性，这是哮喘的主要特征。这些结果表明，粘膜组织中的 NKT 细胞可能会对微生物和含有糖脂的植物产品等物质产生反应，并且 NKT 细胞在调节粘膜组织对环境糖脂的许多免疫反应中可能发挥着先前未曾预料到的关键作用。尽管目前已知只有少数糖脂可以激活NKT细胞，但我们认为某些食物，例如花生，可能含有可以刺激NKT细胞的糖脂，从而激活先天性和适应性粘膜免疫反应。因此，我们建议从花生中纯化并鉴定可直接激活NKT细胞的糖脂。我们相信花生糖脂可以激活NKT细胞，从而激活先天免疫机制，从而大大增强对花生的适应性免疫。我们将研究小鼠系统以及来自正常和花生过敏个体的人类细胞，检查体外和体内反应。我们与一位杰出的脂质生物化学家合作，在人类和小鼠 NKT 细胞方面拥有丰富的经验。此外，我们已经有了令人兴奋的初步数据证明纯化的花生糖脂确实可以激活NKT细胞，这表明我们的假设是正确的，我们的研究是可行的并且可能产生重要的新信息。我们相信，我们的研究可能会极大地扩展对粘膜部位发生的免疫反应类型以及花生等食物如何诱导导致食物过敏的免疫反应的基本了解。