Immune Basis of FPIES

FPIES 的免疫基础

基本信息

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
项目类别：
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

项目摘要

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.

食物蛋白诱发的小肠结肠炎综合征 (FPIES) 是一种非 IgE 介导的食物过敏，通常发生在婴儿期。 FPIES 因严重呕吐和休克样症状而被认为是过敏急症。摄入致病食物 1-4 小时。急性暴露后 FPIES 的症状在数小时内消失以及长期接触后的天数；胃肠粘膜内窥镜检查和活检并不常规进行的目的是基于对一系列症状的识别来确认诊断。婴儿期的诊断基于临床病史，并进行口服食物挑战 (OFC) 以确定是否已经发生了生长。 OFC 在医院进行，有静脉通路可快速输液复苏。除了资源高度密集之外，它们的可用性也有限，而且极其有限。由于胃肠道症状的严重性，患者和护理人员都会感到不愉快。有一个对更好的诊断方法以及对潜在病理生理学的了解的需求尚未得到满足。在目标 1 中，我们将以 1:2 的比例将参与者随机分配到标准 OFC 或新颖的低剂量多日挑战方案，其中有 FPIES 病史的个体将在第一天接受低剂量（300 毫克蛋白质）OFC 的挑战，我们预计大多数具有活跃 FPIES 的人都能耐受。然后他们将继续每天 300 在家进行总共 7 天的 mg 挑战，同时监测症状。第 8 天，参与者将返回参加重新评估和生物样本收集。如果在家挑战期间没有记录到客观症状，将执行常规 3 g OFC。方案中任何一点的客观症状都将导致方案停止挑战。我们预计大多数对 OFC 做出反应的人会发展得相对温和，但在家给药期间出现客观胃肠道症状（呕吐、腹泻）。在目标 2 中，我们将执行低剂量慢性抗原攻击激活的 T 细胞的高维 T 细胞分析。 FPIES 是与缺乏循环可检测的食物特异性 T 细胞有关，但是在出现症状反应期间是系统性先天免疫细胞激活以及血浆中可检测到的 Th17 细胞因子特征，表明组织驻留 T 细胞的作用。正如在乳糜泻中麸质挑战中观察到的那样，我们期望观察到外周肠道驻留 T 细胞的扩增，以应对多天的食物挑战。我们会排序这些细胞并进行光谱细胞术、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作为 FPIES 中 T 细胞激活和呕吐症状之间的机制联系。来自肠嗜铬细胞（EC）的血清素被认为可以驱动迷走神经传入神经的激活，从而导致呕吐， EC 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检，研究 ECs 通过嘌呤途径释放血清素的免疫调节。成功完成我们的目标将直接改善患者护理并增进我们对 FPIES 的理解。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Untargeted serum metabolomic analysis reveals a role for purinergic signaling in FPIES.

非靶向血清代谢组学分析揭示了 FPIES 中嘌呤能信号传导的作用。

DOI：
发表时间：
2023-03
期刊：
影响因子：
0
作者：
Lozano;Chen, Xin;Dunkin, David;Agashe, Charuta;Baker, Mary Grace;Bird, J Andrew;Molina, Elena;Nowak;Berin, M Cecilia
通讯作者：
Berin, M Cecilia