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， 婴儿期。FPIES被认为是一种过敏性紧急情况，由于严重呕吐和休克样症状， 1-4摄入致病食物的时间FPIES的症状在急性暴露后数小时内消退 慢性暴露后的时间和天数;胃肠道粘膜的内窥镜检查和活检不是常规的 所述诊断是基于对症状群的识别而进行的。 婴儿期的诊断基于临床病史，并进行口服食物激发（OFC）以确定是否 出现了增长。OFC是在医院进行的，有静脉通道，快速液体 复苏术除了高度资源密集型之外，它们的可用性有限， 由于胃肠道症状的严重性，这对患者和护理人员来说是不愉快的。有一个 对更好的诊断方法以及对潜在病理生理学的理解的未满足的需求。 在目标1中，我们将受试者1：2随机分配至标准OFC或新型低剂量多日激发方案， 其中具有FPIES病史的个体将在第1天用低剂量（300 mg蛋白质）OFC激发， 我们希望大多数有活跃FPIES的人都能容忍。然后他们将继续每天300 在家中进行总共7天的mg挑战，同时监测症状。第八天，参加者将返回 重新评估和生物标本采集。如果在家庭攻毒期间未记录到客观症状， 将进行常规的3g OFC。方案任何时间点的客观症状将导致停止 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， 在家给药期间的客观胃肠道症状（呕吐、腹泻）。在目标2中，我们将执行 通过低剂量慢性抗原攻击活化的T细胞的高维T细胞谱。FPIES是 与缺乏循环可检测的食物特异性T细胞有关，然而，在症状反应期间， 是全身性先天免疫细胞激活以及血浆中可检测的Th 17细胞因子特征， 这表明了组织驻留T细胞的作用。正如在乳糜泻中谷蛋白激发所观察到的那样，我们希望 观察到肠道驻留T细胞在外周中的扩增，以响应多日的食物挑战。我们会解决的 这些细胞并进行光谱细胞术、批量RNAseq和单细胞RNAseq，以产生完整的 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 代谢途径作为T细胞活化和FPIES中呕吐症状之间的机制联系。 来自肠嗜铬细胞（EC）的血清素被认为驱动迷走神经传入的激活，导致呕吐， 和EC对FPIES反应期间升高的嘌呤代谢物有反应。在目标3中，我们将使用 胃肠道活组织检查以研究通过嘌呤途径从EC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。