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：
8416327
负责人：
Maria CECILIA BERIN
金额：
$ 39.72万
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/8416327
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 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（例如食物诱发的过敏反应）和非IgE介导的疾病（例如食物蛋白诱发的小肠结肠炎综合征（FPIES））。除了严格避免过敏原外，目前没有推荐的治疗方法。 IgE 介导的过敏和细胞介导的过敏共有一个特征，即存在产生 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将 Th2 细胞置于主要致病作用，但有关诱导机制和效应机制的信息却很少。长期目标是了解如何操纵 T 细胞对食物过敏原的反应以达到治疗目的。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。该假说认为，产生 Th2 或其他致病性细胞因子的炎症 T 细胞在肠粘膜中积聚，当再次暴露于过敏原时，可以通过作用于上皮细胞、平滑肌和感觉神经，直接诱导胃肠道功能障碍。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，将确定治疗食物过敏的创新靶标。为了实现这一目标，将确定人类和实验性 IgE 介导和非 IgE 介导的食物过敏中过敏原特异性 T 细胞的表型。接下来，将使用小鼠和人类样本的体内、离体和体外方法来量化过敏原诱导的 Th2 细胞激活对上皮通透性、分泌和肠道蠕动的直接影响。最后，将确定过敏原特异性 Th2 细胞对胃肠粘膜外在感觉神经支配的影响，并测试感觉神经在食物过敏胃肠道表现中的作用。这项研究的贡献是重大的，因为它将确定 T 细胞介导的胃肠功能障碍的机制，从而确定治疗干预的新靶点。这项研究的重点是所有食物过敏性疾病的共同特征，即食物过敏原特异性 Th2 淋巴细胞，因此我们预计这项研究将与广泛的食物过敏性疾病相关。