Regulation of Food Allergy and Anaphylaxis by IL-33

IL-33 对食物过敏和过敏反应的调节

基本信息

批准号：
8707087
负责人：
PAUL J BRYCE
金额：
$ 35.22万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2014-02-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707087
关键词：
Address Adoptive Transfer Allergens Allergic Allergic Disease Allergy to peanuts Anaphylaxis Antibodies Antigens Arthritis Asthma Automobile Driving Basophils Breeding Bypass Cell Nucleus Cells Coin Communication Data Dendritic Cells Development Disease Eczema Endothelial Cells Environment Epithelial Epithelial Cells Exposure to Family Fibroblasts Food Hypersensitivity Generations Goals Hypersensitivity IgE Immediate hypersensitivity Immune response Immunity Immunization Incidence Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukins Intestines Lead Life Mediating Modeling Molecular Profiling Mus Nature Oral Passive Immunization Patients Peanuts - dietary Prevalence Reaction Recombinants Regulation Reporter Rest Role Route Signal Transduction Site Societies Source T cell response Testing Therapeutic Time Tissues Work allergic response base cell type cytokine environmental allergen feeding improved interest intraperitoneal mast cell member receptor recombinase response

项目摘要

DESCRIPTION (provided by applicant): IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an "alarmin", important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells, have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We wil examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses. These aims are: Specific Aim 1: Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses. Specific Aim 2: Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.

描述（由申请人提供）：IL-33是最近发现的IL-1细胞因子家族的成员。重组IL-33的给药已被证明对各种疾病的疾病具有深远的影响，包括关节炎，感染和过敏，这些疾病通过其受体ST2介导。已经证明了几种不同的细胞类型表达IL-33，我们以及其他细胞类型表明上皮细胞具有较高的组成型表达，并在损伤期间释放它。因此，IL-33已被创造为“警报蛋白”，对组织细胞与免疫反应之间的通信很重要。但是，我们已经证明炎性细胞（例如肥大细胞）在静止水平上较低，但在激活后诱导表达IL-33。这些不同来源的IL-33来源的功能后果尚未被研究，确定这些是我们研究的基础。我们的初步数据确定，ST2也是对过敏原的敏化所必需的当绕过敏化时，可以有效地安装炎症反应。有趣的是，我们的发现表明，ST2仅通过肠道敏化需要，并且通过注射相同的抗原，ST2 KO小鼠能够变得过敏。我们假设上皮细胞是驱动过敏敏化的IL-33的必要来源，而肥大细胞衍生的IL-33是发生敏化后炎症的关键信号。我们将使用我们开发的食物过敏和过敏反应的鼠模型来检查这一假设。由于食物过敏的患病率正在增加，目前几乎没有治疗选择，因此我们的工作有可能促进这些患者的新疗法。我们建议以两个不同的特定目的来检验我们的假设，以解决1）敏化和2）引发过敏反应的总体主题。这些目的是：特定目标1：确定细胞特异性IL-33表达在花生特异性抗体和T细胞反应中的作用。具体目标2：确定IL-33通过其调节组织炎症产生过敏原的机制。