IL-9-producing MC precursor ancestry and function in Food Allergy

产生 IL-9 的 MC 前体血统及其在食物过敏中的功能

基本信息

批准号：
10790853
负责人：
SIMON Patrick HOGAN
金额：
$ 33万
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：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10790853
关键词：
Adoptive Transfer Affect Age Allergen Immunotherapy Allergic Allergic Reaction Allergy to peanuts American Anaphylaxis Antigens Autacoids Basophils Biological Models Biopsy Specimen Bone Marrow CD34 gene Categories Cell Density Cell Lineage Cells Child Clinical Clinical Research Complex Development Duodenum Elements FDA approved Food Food Hypersensitivity Frequencies Genetic Enhancer Element Genetic Transcription Hematopoietic Hospitalization Human IL3 Gene IgE Immune Immunotherapy In Vitro Incidence Individual Inflammatory Interleukin-9 Intervention Knowledge Licensing MADH2 gene Mediating Mediator Metabolic Milk Modeling Molecular Mouse Strains Mucous Membrane Mus NF-kappa B Nuts Outcome Patients Phenotype Population Predisposition Prevalence Prevention Process Proto-Oncogene Protein c-kit Reaction Recording of previous events Regulation Role Science Seminal Series Sesame - dietary Severities Shellfish Signal Pathway Signal Transduction Small Intestines Source Symptoms System Systemic Mastocytosis TSLP gene Testing Th2 Cells Therapeutic Tissues Trees Tryptase Wheat activating transcription factor bZIP Domain crosslink cytokine defined contribution density dietary economic cost egg experimental study food avoidance gastrointestinal gastrointestinal symptom in vitro Model in vivo induced pluripotent stem cell mast cell mouse model oral immunotherapy precursor cell reconstitution soy stem stem cells therapeutic target transcription factor

项目摘要

Food allergy has increased at an alarming rate from 2005-2014 in the US, with a disproportionally higher incidence in children2-5. Clinical symptoms of food allergy (FA) range from mild reactions to severe, potentially lethal anaphylaxis6 and there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option15. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of effective and safe therapies8. Over the last 15 years, our team has made several seminal contributions that unveiled a critical role for IL-9/IL-9R-axis and gastrointestinal (GI) mast cells (MC) load in the eliciting of IgE-mediated food allergy. Consistent with this, we have identified a hypogranular, IL-9 producing MC precursor (MCp9) population that is sufficient for induction of food allergy symptoms in different mice strains. The current gap in knowledge is the cellular origin and cytokine sequelae that underlie the development and function of MCp9s and that the presence of this cell in humans. In preliminary studies we have made several transformative observations: 1) that MCp9s are derived from the bipotential basophil / MC progenitor (FcRI- MCp) and not the committed MC progenitor (FcRI+ MCp), 2) sequence stimulation with TGF and IL-33 is required for the development of MCp9; 3) TGF1 priming for MCp9 formation is associated with SMAD2/3 activation and TGFR1-dependent and 3) IL-33-induction of Il9 expression is NFkB-dependent. Finally, we have developed a iPS-cell derived human hematopoietic culture system and identified human MCp9 cells (CD117+ FcRI+ 7high CD203c- IL-9+) cells and revealed the presence of Tryptase+ IL-9+ cells in duodenal biopsy samples from food allergic individuals. We hypothesize that MCp9 cells are derived from a MC precursor population, induced by sequence-dependent TGFIL-33 signaling axis and regulates GI MC density in food allergy models. To test our hypothesis, we propose three aims: 1) Define MCp9 ancestry in mice and humans; 2) Define the requirement of Il9 CNS25 enhancer element in MCp9 fate determination and function and 3) Define the contribution of MCp9 cells to GI MC tissue density in food Allergy. With respect to the expected outcomes, the studies proposed in Aim I are expected to define murine and human MCp9 ancestry and functionality; 2) Define the involvement of sequential TGF and IL-33 signals in the regulation of the Il9 CNS25 element in MCp9 formation and 3) demonstrate a requirement for MCp9-derived IL- 9 in Food Allergy and define the relationship of this cell with peanut allergy and oral immunotherapy outcomes. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms underpinning GI MC density in food allergy and the requirement of this cell in increased MC tissue density in food allergy, thereby directing the development of new and pre-existing therapeutics for treating food allergy and anaphylaxis.

从 2005 年到 2014 年，美国食物过敏以惊人的速度增加，其中食物过敏的比例高得不成比例。儿童食物过敏 (FA) 的发病率从轻微反应到严重反应不等。致命的过敏反应6，FDA 批准的食物过敏治疗方案有限，需要避免食物仍然是唯一安全的选择15。潜在的食物过敏显然有利于开发有效且安全的疗法8。在过去 15 年中，我们的团队做出了多项开创性贡献，揭示了 IL-9/IL-9R 轴和胃肠 (GI) 肥大细胞 (MC) 负荷引起 IgE 介导的食物过敏。与此一致，我们已经鉴定出无颗粒的hyar、产生IL-9的MC前体(MCp9)群体，其是足以诱导不同品系小鼠的食物过敏症状。目前的知识差距是。细胞起源和细胞因子后遗症是 MCp9 发育和功能的基础，并且存在人体中的这种细胞。在初步研究中，我们做了一些变革性的观察：1）MCp9s 是衍生的来自双能嗜碱性粒细胞/MC 祖细胞 (FcRI- MCp)，而不是定型 MC 祖细胞 (FcRI+ MCp)， 2) MCp9 的发育需要 TGF 和 IL-33 的序列刺激；3) TGF1 引发 MCp9 的形成与 SMAD2/3 激活和 TGFβR1 依赖性以及 3) IL-33 诱导的 Il9 有关最后，我们开发了一种 iPS 细胞衍生的人类造血培养物。系统并鉴定了人 MCp9 细胞 (CD117+ FcRI+ 7high CD203c- IL-9+) 细胞并揭示了其存在来自食物过敏个体的十二指肠活检样本中的类胰蛋白酶 + IL-9+ 细胞的数量我们与 MCp9 进行了斗争。细胞源自 MC 前体群体，由序列依赖性 TGFIL-33 信号轴诱导并调节食物过敏模型中的 GI MC 密度为了检验我们的假设，我们提出三个目标：1) 定义。小鼠和人类的 MCp9 血统；2) 确定 MCp9 命运中 Il9 CNS25 增强子元件的要求测定和功能，以及 3) 定义 MCp9 细胞对食物过敏中 GI MC 组织密度的贡献。关于预期结果，目标 I 中提出的研究预计将定义小鼠和人类 MCp9 祖先和功能；2) 定义连续 TGFβ 和 IL-33 信号在 MCp9形成中Il9 CNS25元件的调节和3)证明了对MCp9衍生的IL-的需要 9 食物过敏并定义了该细胞与花生过敏和口服免疫治疗结果的关系。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食物过敏中胃肠道MC密度的潜在分子机制的了解和食物过敏时该细胞需要增加 MC 组织密度，从而直接导致用于治疗食物过敏和过敏反应的新疗法和现有疗法。