Immune Basis of FPIES

FPIES 的免疫基础

• 批准号: 10502608
• 负责人: Maria CECILIA BERIN
• 金额: $ 85.63万
• 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/10502608
• 关键词: Acute; Adenosine; Allergic; Antigens; Biological Markers; Biopsy; Blood; Caregivers; Celiac Disease; 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; Safety; Serotonin; Severities; Shock; Supervision; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Vomiting; antagonist; antigen challenge; antigen-specific T cells; base; 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; 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.

食物蛋白诱导的小肠结肠炎综合征(FPIES)是一种非IgE介导的食物过敏，通常起病于 婴儿期。FIES被认为是由于严重呕吐和休克样症状引起的过敏性紧急情况 摄入致病食物1-4小时。急性暴露后数小时内症状消失 和慢性暴露后的几天；胃肠粘膜的内窥镜检查和活检不是常规的 用于基于对症状群的识别来确认诊断。 婴儿期的诊断是基于临床病史，并进行口服食物挑战(OFC)以确定是否 结果已经发生了。OFC是在医院进行的，静脉通路到位，以获得快速液体 复苏。除了高度资源密集型外，它们的可用性有限，而且非常 由于胃肠道症状严重，对患者和照顾者来说都不舒服。有一个 对更好的诊断方法的需求尚未得到满足，以及对潜在的病理生理学的了解。 在目标1中，我们将参与者1：2随机分配到标准OFC或一种新的低剂量多天挑战方案， 有FPIES病史的人将在第一天接受低剂量(300毫克蛋白质)OFC的挑战， 我们预计大多数FIE活跃的人都能容忍这种情况。然后，他们将继续每天300人 镁在家中挑战，共7天，同时监测症状。在第8天，参与者将返回参加 重新评估和生物标本收集。如果在主场挑战期间没有记录到客观症状， 将执行常规的3g OFC。在协议的任何点上出现客观症状都会导致停止 挑战。我们预计大多数对OFC有反应的人将发展为相对温和的但 目的在家中给药时出现胃肠道症状(呕吐、腹泻)。在《目标2》中，我们将表演 低剂量慢性抗原攻击激活的T细胞的高维T细胞图谱。FPIES是 与缺乏循环中可检测到的食物特异性T细胞有关，但在症状反应期间 在血浆中检测到系统性先天免疫细胞激活和Th17细胞因子信号， 这表明驻留在组织中的T细胞发挥了作用。正如在乳糜泻中观察到的面筋挑战一样，我们预计 看到外周肠道驻留T细胞的扩张，以应对持续数天的食物挑战。我们将对 并执行光谱细胞术、批量RNAseq和单细胞RNAseq以生成完整的 了解这些细胞在FPIES反应中的作用。在目标3中，我们将研究嘌呤的作用 代谢途径是T细胞活化与呕吐症状之间的机制联系。 肠嗜铬细胞(EC)中的5-羟色胺被认为驱动迷走神经传入的激活，导致呕吐， 和EC对在FPIES反应中升高的嘌呤代谢物有反应。在目标3中，我们将使用 胃肠活检研究血管内皮细胞通过嘌呤途径释放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，并促进我们对FPIES的理解。