Immune Basis of FPIES

FPIES 的免疫基础

• 批准号: 10688156
• 负责人: Maria CECILIA BERIN
• 金额: $ 80.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-23 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688156
• 关键词: Acute; Adenosine; Allergic; Antigens; Biological Markers; Biopsy; Blood; Caregivers; Celiac Disease; Cell Separation; Cells; Chronic; Clinical; Collection; Critical Pathways; Cytometry; Diagnosis; Diagnostic; Diagnostic tests; Diarrhea; Disease; Disease Pathway; Dose; Double-Blind Method; Emergency Situation; Endoscopy; Enterochromaffin Cells; Evaluation; Food; Food Hypersensitivity; Food Protein-Induced Enterocolitis Syndrome; Frequencies; Functional disorder; Gastrointestinal tract structure; Gluten; Health Services Accessibility; Home; Hospitals; Hour; Human; IV Fluid; Immune; Immune response; Improve Access; Individual; Ingestion; Intravenous; Link; Liquid substance; Mediating; Monitor; Mucous Membrane; Nature; Ondansetron; Oral; Participant; Pathway interactions; Patient Care; Patients; Phenotype; Plasma; Proteins; Protocols documentation; Provider; Purines; Purinoceptor; Randomized; Reaction; Recording of previous events; Reflex action; Regulation; Resolution; Resources; Resuscitation; Role; Serotonin; Severities; Shock; Sorting; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Vomiting; antagonist; antigen challenge; antigen-specific T cells; cytokine; food antigen; food challenge; gastrointestinal; gastrointestinal symptom; high dimensionality; immune activation; immunoregulation; improved; infancy; metabolomics; novel; peripheral blood; primary outcome; purine metabolism; receptor; response; safety assessment; single cell analysis; single-cell RNA sequencing; transcriptome sequencing

Food protein induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with a usual onset in infancy. FPIES is recognized as an allergic emergency due to severe vomiting, and shock-like symptoms within 1-4 hours of ingestion of the causative food. Symptoms of FPIES resolve within hours following acute exposure and days following chronic exposure; endoscopy and biopsy of gastrointestinal mucosa are not routinely performed for the confirmation of diagnosis that is based on the recognition of the constellation of symptoms. Diagnosis in infancy is based on clinical history, and oral food challenges (OFC) are performed to determine if outgrowth has occurred. OFC are performed in hospital, with intravenous access in place for rapid fluid resuscitation. In addition to being highly resource-intensive, they are limited in availability and extremely unpleasant for the patient and the caregivers, due to the severity of the gastrointestinal symptoms. There is an unmet need for better approaches for diagnosis, as well as an understanding of the underlying pathophysiology. In Aim 1, we will randomize participants 1:2 to standard OFC or a novel low-dose multi-day challenge protocol, in which individuals with a history of FPIES will be challenged on Day 1 with a low-dose (300 mg protein) OFC, which we expect to be tolerated by most individuals with active FPIES. They will then continue with a daily 300 mg challenge at home for a total of 7 days, while monitoring symptoms. On day 8, participants will return for a re-evaluation and biospecimen collection. If no objective symptoms were recorded during the at-home challenge, a regular 3 g OFC will be performed. Objective symptoms at any point of the protocol will result in stopping of the challenge. We anticipate that the majority of those who will react to the OFC will develop relatively mild but objective gastrointestinal symptoms (vomiting, diarrhea) during the at home dosing. In Aim 2, we will perform high dimensional T cell profiling of T cells activated by the low dose chronic antigen challenge. FPIES is associated with a lack of circulating detectable food-specific T cells, however during symptomatic reactions there is a systemic innate immune cell activation as well as a Th17 cytokine signature detectable in the plasma, suggesting a role for tissue resident T cells. As is observed with gluten challenge in celiac disease, we expect to see an expansion of gut-resident T cells in the periphery in response to a multi-day food challenge. We will sort these cells and perform spectral cytometry, bulk RNAseq, and single cell RNAseq to generate a full understanding of the role of these cells in FPIES reactions. In Aim 3, we will examine the role of the purine metabolism pathway as the mechanistic link between T cell activation and vomiting symptoms in FPIES. Serotonin from enterochromaffin cells (EC) is thought to drive activation of vagal afferents leading to vomiting, and EC are responsive to purine metabolites that are elevated during FPIES reactions. In Aim 3, we will use gastrointestinal biopsies to study the immune regulation of serotonin release from ECs via the purine pathway. Successful completion of our aims will directly improve patient care and advance our understanding of FPIES.

食品蛋白诱导的小肠结肠炎综合征（FPIE）是一种非IGE介导的食物过敏，通常发作 婴儿期。由于严重的呕吐，FPIE被认为是过敏的紧急事件，并且在 1-4小时摄取因果食品。急性暴露后数小时内解决FPIE的症状 和慢性暴露后的几天；胃肠道粘膜的内窥镜检查和活检并非常规 为了确认诊断的确认，这是基于对症状星座的识别。 婴儿期的诊断是基于临床病史，并且（OFC）进行口服食物挑战以确定是否是否 出现已经发生。 OFC在医院进行，并有静脉输入以进行快速流体 复苏。除了高度资源密集型外，它们的可用性和极其极为有限 由于胃肠道症状的严重程度，患者和护理人员不愉快。有一个 对诊断的更好方法以及对潜在的病理生理学的理解未满足。 在AIM 1中，我们将将参与者1：2随机为标准OFC或新型的低剂量多日挑战协议， 其中有具有FPIE病史的个体将在第1天通过低剂量（300 mg蛋白）OFC挑战 我们期望大多数活跃FPIE的人能够容忍这一点。然后，他们将继续每天300 毫克在家中挑战7天，同时监测症状。在第8天，参与者将返回 重新评估和生物循环收集。如果在家挑战期间没有记录客观症状， 将执行常规3 g OFC。协议的任何时候客观症状都将导致停止 挑战。我们预计，大多数会对OFC做出反应的人会发展相对温和，但 在家给药期间，客观胃肠道症状（呕吐，腹泻）。在AIM 2中，我们将表演 低剂量慢性抗原挑战激活的T细胞的高维T细胞分析。 fpies是 与缺乏可检测可检测的食物特异性T细胞有关，但是在有症状的反应期间 是系统性的先天免疫细胞激活，以及在血浆中可检测到的Th17细胞因子特征， 暗示组织驻留T细胞的作用。正如腹腔疾病中面筋挑战所观察到的那样，我们期望 请参阅外围肠道居民T细胞的扩展，以应对多天的食物挑战。我们会排序 这些细胞并执行光谱细胞仪，大量RNASEQ和单细胞RNASEQ，以生成完整的 了解这些细胞在FPIE反应中的作用。在AIM 3中，我们将研究嘌呤的作用 代谢途径是FPIE中T细胞激活与呕吐症状之间的机械联系。 肠球毒细胞（EC）的5-羟色胺被认为可以驱动迷走神经传入的激活，导致呕吐， EC对FPIS反应期间升高的嘌呤代谢产物有反应。在AIM 3中，我们将使用 胃肠道活检以研究通过嘌呤途径从ECS释放5-羟色胺的免疫调节。 成功完成我们的目标将直接改善患者护理，并提高我们对FPIE的理解。