Role of T cells in gastrointestinal manifestations of food allergy

T细胞在食物过敏胃肠道表现中的作用

基本信息

批准号：
8604671
负责人：
Maria CECILIA BERIN
金额：
$ 42.04万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604671
关键词：
Abdominal Pain Address Adult Adverse reactions Affect Afferent Neurons Allergens Allergic Allergic Disease Allergic inflammation Anaphylaxis CD4 Positive T Lymphocytes Cells Child Chronic Clinical Data Development Diarrhea Disease Enterocolitis Epithelial Epithelial Cells Exposure to Failure to Thrive Food Food Hypersensitivity Functional disorder Gastrointestinal Diseases Gastrointestinal Physiology Gastrointestinal tract structure Goals Hemorrhagic colitis Hour Human Hypersensitivity Hypoalbuminemia Hypotension IgE Immune In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-13 Interleukin-4 Interleukin-5 Intestinal Motility Intestinal Mucosa Intestines Ions Knowledge Lead Life Lymphocyte Measurable Measures Mediating Mediator of activation protein Methodology Modeling Monoclonal Antibody HuM291 Mucous Membrane Mus Muscle function Nerve Neuropeptides Outcome Pathway interactions Patients Permeability Phenotype Proteins Public Health Quality of life Research Role SCID Mice Sensory Smooth Muscle Specimen Syndrome T cell response T-Cell Activation T-Lymphocyte TNF gene Testing Th2 Cells Therapeutic Therapeutic Intervention Vomiting Work afferent nerve base cell motility cytokine eosinophilic gastroenteritis food allergen gastrointestinal gastrointestinal function in vivo innovation lymph nodes mucosal vaccination nerve supply new therapeutic target novel response trafficking

项目摘要

DESCRIPTION (provided by applicant): Food allergy includes both IgE-mediated disorders such as food-induced anaphylaxis and non-IgE- mediated disease such as food protein induced enterocolitis syndrome (FPIES). There are no currently recommended treatments beyond strict allergen avoidance. A feature shared by IgE-mediated and cell- mediated allergy is the presence of food allergen-specific Th2 cells producing IL-4, IL-13 and TNF1. Although our current understanding of various food allergic disorders places the Th2 cell in a central pathogenic role, there is a paucity of information about mechanisms of induction as well as effector mechanisms. The long-term goal is to understand how the T cell response to food allergens can be manipulated for therapeutic purposes. The objective of this proposal is to identify the pathogenic mechanisms of allergen-specific T cells in the gastrointestinal (GI) tract with emphasis on non-IgE- mediated FA. The hypothesis is that inflammatory T cells producing Th2 or other pathogenic cytokines accumulate in the gut mucosa and upon re-exposure to the allergen can directly induce GI dysfunction by acting on epithelial cells, smooth muscle, and sensory nerves. The rationale for the proposed research is that by understanding the phenotype and function of allergen-specific Th2 lymphocytes in the gastrointestinal tract, innovative targets will be identified for treatment of food allergy. To address this objective, the phenotype of allergen-specific T cells in human and experimental IgE-mediated and non-IgE- mediated food allergy will be determined. Next, the direct effect of allergen-induced Th2 cell activation on epithelial permeability, secretion, and intestinal motility will be quantified using in vivo, ex vivo and in vitro methodologies with murine and human specimens. Finally, the impact of allergen-specific Th2 cells on extrinsic sensory innervations of the gastrointestinal mucosa will be identified, and the role of sensory nerves in gastrointestinal manifestations of food allergy will be tested. The contribution of this research is significant because it will identify mechanisms involved in T cell-mediated gastrointestinal dysfunction, and thereby identifies new targets for therapeutic intervention. This research focuses on a shared feature of all food allergic disorders, the food allergen-specific Th2 lymphocyte, and therefore we anticipate that this research will be relevant to a broad spectrum of food allergic disorders.

描述（由申请人提供）：食物过敏包括IgE介导的疾病，例如食物诱导的过敏反应和非IGE介导的疾病，例如食品蛋白诱导的诱导的小肠结肠炎综合征（FPIES）。除了严格避免过敏原外，目前尚无建议治疗。 IgE介导的和细胞介导的过敏的特征是存在产生IL-4，IL-13和TNF1的食物过敏原特异性Th2细胞。尽管我们目前对各种食物过敏性疾病的理解使TH2细胞扮演了中心致病作用，但有关诱导机制和效应机制的信息很少。长期目标是了解如何用于治疗目的对食物过敏原的T细胞反应。该提案的目的是确定胃肠道（GI）中过敏原特异性T细胞的致病机制，重点是非IGE-介导的FA。假设是，产生Th2或其他致病细胞因子在肠道粘膜中积累并在过敏原中暴露后会直接通过作用于上皮细胞，平滑肌和感觉神经来直接诱导GI功能障碍。拟议研究的基本原理是，通过了解胃肠道中过敏原特异性Th2淋巴细胞的表型和功能，将确定创新靶标以治疗食物过敏。为了解决这一目标，将确定过敏原特异性T细胞的表型，并确定IgE介导的和非IgE介导的食物过敏。接下来，使用体内，体内和体外方法论用鼠和人类标本来量化过敏原诱导的Th2细胞激活对上皮渗透性，分泌和肠运动的直接作用。最后，将鉴定出过敏原特异性Th2细胞对胃肠道粘膜外部感觉神经的影响，并将测试感觉神经在食物过敏的胃肠道表现中的作用。这项研究的贡献很大，因为它将确定与T细胞介导的胃肠道功能障碍有关的机制，从而确定治疗干预的新靶标。这项研究着重于所有食物过敏性疾病，食物过敏原特异性TH2淋巴细胞的共同特征，因此我们预计这项研究将与各种食物过敏疾病有关。