Role of T cells in gastrointestinal manifestations of food allergy

描述(申请人提供)：食物过敏既包括由IgE介导的疾病，如食物过敏反应，也包括非IgE介导的疾病，如食物蛋白诱导的小肠结肠炎综合征(FPIES)。目前，除了严格避免过敏原外，没有推荐的治疗方法。IgE介导和细胞介导的过敏症的一个共同特征是存在食物过敏原特异性Th2细胞，产生IL-4、IL-13和TNF1。尽管我们目前对各种食物过敏障碍的理解将Th2细胞置于中心致病作用，但关于诱导机制以及效应机制的信息很少。长期目标是了解T细胞对食物过敏原的反应如何被操纵以达到治疗目的。这项建议的目的是确定胃肠道(GI)中变应原特异性T细胞的致病机制，重点是非IgE介导的FA。假说是产生Th2或其他致病细胞因子的炎性T细胞在肠粘膜积聚，当再次暴露于过敏原时，可通过作用于上皮细胞、平滑肌和感觉神经直接导致胃肠道功能障碍。这项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点。为了解决这一目标，将确定人和实验中IgE介导的和非IgE介导的食物过敏中变应原特异性T细胞的表型。接下来，我们将使用体内、体外和体外的方法，用小鼠和人类标本来量化过敏原诱导的Th2细胞激活对上皮通透性、分泌物和肠道运动的直接影响。最后，将确定过敏原特异性Th2细胞对胃肠粘膜外源性感觉神经支配的影响，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障碍的一个共同特征，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障碍相关。 公共卫生相关性：拟议的研究与公共健康相关，因为所研究的途径可能为抑制粘膜T细胞反应提供新的治疗靶点。这项研究不仅与食物过敏性疾病有关，而且与免疫介导的胃肠道疾病，如炎症性肠病和粘膜疫苗接种有关。

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the studied pathways are likely to provide new therapeutic targets for suppression of the mucosal T cell response. This research has relevance not only to food allergic disorders, but also to immune-mediated gastrointestinal disorders such as inflammatory bowel disease and to mucosal vaccination.