Identification and validation of HLA class II T cell epitopes in shrimp allergy

虾过敏中 HLA II 类 T 细胞表位的鉴定和验证

• 批准号: 7893491
• 负责人: JULIO Cesar DELGADO
• 金额: $ 22.48万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893491
• 关键词: Adult; Affinity; Alleles; Allergens; American; Antigen Presentation; Applications Grants; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cells; Complex; Development; Epitopes; Fluorescence Polarization; Food; Food Hypersensitivity; Goals; Hypersensitivity; IgE; Immunological Diagnosis; In Vitro; Individual; Ingestion; Kinetics; Mediating; Patients; Peptides; Peripheral Blood Mononuclear Cell; Population; Production; Proteins; Reaction; Research; Shellfish; Shrimp; Specificity; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Testing; Tropomyosin; Vaccine Therapy; Validation; base; cytokine; design; enzyme linked immunospot assay; immunogenic; insight; peptide based vaccine; research study; response; tool

DESCRIPTION (provided by applicant): Food allergy is an increasing problem in the American population. Among adults, the most frequent cause of food allergy is the ingestion of shellfish. Currently, the solely therapy for shellfish allergy is the avoidance of the food. Recent studies have concluded that tropomyosin is the predominant allergen in shellfish allergy. Shellfish allergy is an immediate-type hypersensitivity reaction to tropomyosin that is mediated by IgE. Na¿ve CD4 T cell recognition of antigenic tropomyosin peptides presented in the context of HLA class II molecules is thought to be a key component in the mechanism of sensitization and production of IgE. Specific subsets of activated CD4 T cells, particularly TH2 cells, favor the production of IgE. Little is known about the specific CD4 T cell tropomyosin-derived epitopes and mechanisms of antigen presentation that selectively evoke TH2 cells in patients with shellfish allergy. The aims of this exploratory grant application are to identify and validate CD4 T cell tropomyosin-derived epitopes and to characterize CD4 T cell responses in individuals with shellfish allergy upon stimulation with HLA class II-tropomyosin-derived peptides. The specific hypothesis behind the proposed research is that HLA class II molecules bind sets of promiscuous tropomyosin-derived peptides and that differences in the binding kinetics of HLA class II-peptide complexes influence the differentiation of na¿ve CD4 T cells into distinct CD4 T cell subsets (i.e. TH2 cells) that drive IgE-mediated shellfish allergy. In vitro binding assays are proposed to identify potential CD4 T cell epitopes from shellfish tropomyosin and ex-vivo functional assays will be performed to validate immunogenic CD4 T cell epitopes. Further characterization of antigenic peptide binding to HLA class II molecules in terms of binding kinetics and cytokine production are proposed to assess peptide-HLA binding kinetics and its relationship to allergenicity in terms of na¿ve CD4 T cell activation. Taken all together, the experiments proposed in this application will allow the identification of a panel of common peptides binding to different HLA class II molecules that will facilitate the development of epitope-based tolerizing therapies and immunodiagnostic tools in patients with shellfish allergy across different populations. The experiments proposed will also provide critical insights about the immunological mechanisms of antigen presentation that selectively evoke CD4 TH2 cell responses in patients with shellfish allergy. Shrimp allergy, the most frequent cause of food allergy in adults, is an immediate-type hypersensitivity reaction to tropomyosin. Currently, the solely therapy for shrimp allergy is the avoidance of the food. The proposed experiments will identify peptides derived from shrimp tropomyosin and recognized by T cells. The results of this study will facilitate the development of peptide-based vaccine therapies in patients with shrimp allergy.

描述（应用程序提供）：食物过敏是美国人群中日益加剧的问题。在成年人中，食物过敏的最常见原因是摄入贝类。目前，唯一的贝类过敏疗法是避免食物。最近的研究得出的结论是，肌球蛋白是贝类过敏中的主要过敏原。贝类过敏是由IgE介导的直接型对肌动蛋白的超敏反应。在HLA II类分子中提出的抗原型肌球蛋白petides的na�VECD4 T细胞识别被认为是敏感性和产生IgE机制的关键组成部分。活化的CD4 T细胞（尤其是TH2细胞）的特定子集有利于产生IgE。关于特定的CD4 T细胞tropomyosin衍生的表位和抗原表现的机制知之甚少，抗原表现的机制有选择地引起贝类过敏患者的Th2细胞。该探索性赠款应用的目的是识别和验证CD4 T细胞tropomyosin衍生的表位，并在用HLA II类 - 肌动蛋白衍生的肽刺激时表征患有贝类过敏的个体中CD4 T细胞反应。 The specific hypothesis behind the proposed research is that HLA class II molecules bind sets of promiscuous tropomyosin-derived peptides and that differences in the binding kinetics of HLA class II-peptide complexes influence the differentiation of na¿ ve CD4 T cells into distinct CD4 T cell subsets (i.e. TH2 cells) that drive IgE-mediated shellfish allergy.提出了体外结合测定，以鉴定贝类tropomyosin的潜在CD4 T细胞表位，并将进行前体功能测定以验证免疫原性CD4 T细胞表位。提出，就结合动力学和细胞因子产生的抗原肽与HLA II类分子结合的进一步表征，以评估肽-HLA结合动力学及其与过敏性的关系，以NATO CD4 T细胞活化。全力以赴，本应用中提出的实验将允许鉴定与不同HLA II类分子结合的一组公共肽，这些肽将促进基于贝类过敏的贝类过敏的患者在患有贝类的患者中基于表位基于表位的耐受疗法和免疫诊断工具的发展。提出的实验还将提供有关抗原呈递的免疫学机制的关键见解，这些抗原表现有选择地引起贝类过敏患者的CD4 TH2细胞反应。 虾过敏是成人食物过敏的最常见原因，是对肌动蛋白的直接型超敏反应。目前，虾过敏的唯一治疗是避免食物。提出的实验将鉴定出源自虾真肌球蛋白并被T细胞识别的肽。这项研究的结果将促进虾过敏患者的基于胡椒的疫苗疗法的发展。