Pro-Type 2 Goblet Cell Antigen Passages in Food Sensitization and Reactivity

Pro-Type 2 杯状细胞抗原在食品致敏和反应中的传代

基本信息

批准号：
10752964
负责人：
SIMON Patrick HOGAN
金额：
$ 55.06万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-04 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752964
关键词：
Ablation Adjuvant Adult Affect Allergic Allergic Reaction Allergy to peanuts American Anaphylaxis Antigen-Presenting Cells Antigens Basophils CD3 Antigens CD4 Positive T Lymphocytes Cell Communication Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Child Cholera Toxin Clinical Complex Development Exposure to FDA approved Food Food Hypersensitivity Frequencies Funding Gastrointestinal tract structure Genes Genetic Goblet Cells Human IL18 gene IgE Immune Immune Tolerance Immunologics Individual Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Knowledge Lamina Propria Link Mechanics Mediating Milk Modeling Molecular Mus Nuts Oral Organism Organoids Outcome Pathogenicity Pattern Phenotype Population Prevalence Prevention Process Production Property Proto-Oncogene Protein c-kit Reaction Reporter Role Sesame - dietary Shellfish Signal Induction Signal Pathway Signal Transduction Skin Skin injury Small Intestines System T cell response TSLP gene Technology Testing Th2 Cells Therapeutic Trees Tropism Visit Wheat conditioning crosslink cytokine dietary economic cost egg filaggrin food allergen food antigen food avoidance gastrointestinal imprint intestinal epithelium mast cell mouse model recruit response skin barrier soy therapeutic target two photon microscopy

项目摘要

Project Summary The U.S. Center for Disease Control and Prevention estimates of up to 6 million American children with food allergies (roughly 2 in every classroom) at an economic cost of ~$25 billion per year. Currently, there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of new effective and safe therapies8. Over the last funded period our team identified “canonical” goblet cell antigen passages (GAPs) that act to deliver dietary antigens to discrete immunological niches and imprint antigen presenting cells (APCs) with tolerogenic properties to promote immune tolerance. Furthermore, we showed that the food allergic condition was associated with altered gut antigen passage patterning and landscape. These IL-13/IL-4R-dependent “non-canonical” antigen passages were required for induction of IgE-MC reactions. In preliminary studies we demonstrate that systemic activation of the IL-13/IL-4R-signaling pathway is sufficient to promote the outgrowth of SI pro-type-2 GC subpopulation, which express genes associated with dietary antigen recognition and a distinct pro-type-2 inflammatory phenotype and form antigen passages. Strikingly, we provide a link between disruption of skin barrier and pro-Type 2 cytokine production with increased gut IL-13-producing ILC2 cells and a shift in gastrointestinal antigen passage landscape from the “canonical” to “non-canonical” antigen passages. The current gap in knowledge is the requirement of pro-type-2 GCs to food allergen passage and directing the allergic inflammatory response to the gut (allergic gut tropism) and priming for food reactivity. We hypothesize that SI pro-type 2 GCs act as non-canonical antigen passages, drive allergic gut tropism and clinical reactivity to foods. To test our hypothesis, we propose three specific Aims (SA); SA1) Define the role of systemic Type-2 signals in GI pro-type 2 GC-antigen passage formation; SA2) Define the role of GI pro-type 2 GC antigen passages in allergic gut tropism and SA3) Define the requirement of GI pro-type 2 GC antigen passage-induced allergic gut tropism in food reactivity. With respect to the expected outcomes, the studies proposed in SA1 are expected to demonstrate GI pro-type 2 GC antigen passages; SA2 demonstrate that GI pro-type 2 GCs direct antigens to sensitizing LP-DC populations and recruit the food antigen-specific CD4+ Th2 cell response to GI tract and SA3) identify the requirement for GI pro-type 2 GCs in allergic gut tropism and clinical reactivity. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms of dietary food allergen passage across the intestinal epithelium underpinning a critical role for GI pro-type 2 GCs in allergic gut tropism and food reactivity and warrant therapeutic targeting of pro-type 2 GCs for prevention of food allergic reactions.

项目概要美国疾病控制和预防中心估计，多达 600 万美国儿童患有此病食物过敏（每个教室大约有 2 人），每年造成的经济损失约为 250 亿美元。 FDA 批准的食物过敏治疗方案有限，避免进食仍然是唯一安全的选择。显然，更好地了解食物过敏背后的免疫机制和信号通路有理由开发新的有效且安全的疗法8。在上一个资助期间，我们的团队确定了起作用的“规范”杯状细胞抗原通道（GAP）将饮食抗原递送至离散的免疫生态位并用印记抗原呈递细胞（APC）促进免疫耐受的致耐受性此外，我们还发现食物过敏状况。与改变肠道抗原通道模式和景观有关，这些IL-13/IL-4Rα依赖性。诱导 IgE-MC 反应需要“非规范”抗原传代。在初步研究中，我们证明 IL-13/IL-4Rα 信号通路的系统激活是足以促进 SI pro-2 型 GC 亚群的生长，该亚群表达与饮食抗原识别和独特的 pro-2 型炎症表型并形成抗原通道。引人注目的是，我们发现皮肤屏障的破坏与前 2 型细胞因子的产生之间存在联系，随着细胞因子的增加肠道产生IL-13的ILC2细胞以及胃肠道抗原通道格局从“规范”到“规范”的转变 “非规范”抗原通道目前的知识空白是前 2 型 GC 对食物的要求。过敏原通道并将过敏性炎症反应引导至肠道（过敏性肠道趋向性）和启动用于食物反应性。我们追求 SI 前型 2 GC 作为非典型抗原通道，驱动过敏性肠道趋向性为了检验我们的假设，我们提出了三个具体目标 (SA)； GI 原型 2 GC 抗原通道形成中的系统 2 型信号的影响 SA2) 定义 GI 原型的作用； 2 过敏性肠向性和 SA 中的 GC 抗原通道3) 定义 GI 前型 2 GC 抗原的要求就预期结果而言，研究显示了通道诱导的食物反应性肠道过敏倾向。 SA1 中提出的预计将证明 GI 前型 2 GC 抗原传代；SA2 证明 GI 前型 2 GC 将抗原引导至致敏 LP-DC 群体并招募食物抗原特异性 CD4+ Th2 细胞对胃肠道和 SA3 的反应，确定过敏性肠道趋向性中对胃肠道原型 2 GC 的需求，以及临床反应性。成功完成拟议的研究将为我们的研究提供新的实质性出发点目前对膳食食物过敏原通过的潜在分子机制的了解肠上皮支持 GI 前型 2 GC 在过敏性肠道趋向性和食物反应性中的关键作用并保证以 2 型 GC 为治疗靶点来预防食物过敏反应。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulation of intestinal epithelial CFTR-dependent Cl- ion transport and paracellular barrier function drives gastrointestinal symptoms of food-induced anaphylaxis in mice.

肠上皮 CFTR 依赖性氯离子转运和细胞旁屏障功能的失调导致小鼠食物诱发过敏反应的胃肠道症状。

DOI：
发表时间：
2021-01
期刊：
影响因子：
8
作者：
Yamani, Amnah;Wu, David;Ahrens, Richard;Waggoner, Lisa;Noah, Taeko K;Garcia;Ptaschinski, Catherine;Parkos, Charles A;Lukacs, Nicholas W;Nusrat, Asma;Hogan, Simon P
通讯作者：
Hogan, Simon P

Eosinophilic esophagitis: Immune mechanisms and therapeutic targets.

嗜酸性粒细胞性食管炎：免疫机制和治疗靶点。

DOI：
发表时间：
2022-10
期刊：
影响因子：
0
作者：
Khokhar, Dilawar;Marella, Sahiti;Idelman, Gila;Chang, Joy W;Chehade, Mirna;Hogan, Simon P
通讯作者：
Hogan, Simon P

C5a receptor 1-/- mice are protected from the development of IgE-mediated experimental food allergy.

C5a 受体 1-/- 小鼠可免受 IgE 介导的实验性食物过敏的影响。

DOI：
发表时间：
2019-04
期刊：
影响因子：
12.4
作者：
Kordowski, Anna;Reinicke, Anna T;Wu, David;Orinska, Zane;Hagemann, Philipp;Huber;Lee, Jee;Wang, Yui;Hogan, Simon P;Köhl, Jörg
通讯作者：
Köhl, Jörg

IL-13-induced STAT3-dependent signaling networks regulate esophageal epithelial proliferation in eosinophilic esophagitis.

IL-13 诱导的 STAT3 依赖性信号网络调节嗜酸性食管炎中的食管上皮增殖。

DOI：
发表时间：
2023-12
期刊：
影响因子：
0
作者：
Marella, Sahiti;Sharma, Ankit;Ganesan, Varsha;Ferrer;Krempski, James W;Idelman, Gila;Clark, Sydney;Nasiri, Zena;Vanoni, Simone;Zeng, Chang;Dlugosz, Andrej A;Zhou, Haibin;Wang, Shaomeng;Doyle, Alfred D;Wright, Benjamin L;Spenc
通讯作者：
Spenc

Uridine diphosphate-glucose/P2Y14R axis is a nonchemokine pathway that selectively promotes eosinophil accumulation.

尿苷二磷酸-葡萄糖/P2Y14R轴是选择性促进嗜酸性粒细胞积累的非趋化因子途径。