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

• 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
• 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

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，美国的食物过敏以惊人的速度增加， 儿童发病率2 -5。食物过敏（FA）的临床症状范围从轻度反应到严重反应， 致命的过敏反应6，FDA批准的食物过敏治疗选择有限，避免食物 是唯一安全的选择15.更好地了解免疫机制和信号通路 潜在的食物过敏显然是有必要的，以允许开发有效和安全的疗法8。 在过去的15年里，我们的团队做出了几项开创性的贡献，揭示了 IL-9/IL-9 R轴和胃肠道（GI）肥大细胞（MC）负荷在IgE介导的食物过敏中的诱发作用 与此相一致，我们已经鉴定了一种低颗粒的、产生IL-9的MC前体（MCp 9）群体， 足以在不同的小鼠品系中诱导食物过敏症状。目前的知识差距是 细胞起源和细胞因子后遗症是MCp 9的发育和功能的基础， 这种细胞在人类身上的作用。 在初步的研究中，我们已经做了几个变革性的观察：1）MCp 9是衍生的， 来自双能嗜碱性粒细胞/ MC祖细胞（Fc β RI- MCp）而不是定向MC祖细胞（Fc β RI+ MCp）， 2)用TGF β 1和IL-33的序列刺激是MCp 9的发育所必需的; 3）TGF β 1引发MCp 9的发育。 MCp 9的形成与SMAD 2/3激活和TGF β 1依赖性和3）IL-33诱导的IL 9相关 表达是NF κ B依赖性的。最后，我们开发了iPS细胞衍生的人造血培养物， 系统，并鉴定了人MCp 9细胞（CD 117 + FcCRRI + CD 203 c-IL-9+）细胞，并揭示了存在 食物过敏个体十二指肠活检样本中类胰蛋白酶+ IL-9+细胞的百分比。我们假设MCp 9 细胞来源于MC前体群体，由序列依赖性TGF β 1/IL-33信号传导轴诱导 并在食物过敏模型中调节GI MC密度。为了验证我们的假设，我们提出了三个目标：1）定义 2）确定MCp 9命运中Il 9 CNS 25增强子元件的需要 确定和功能，以及3）定义食物过敏中MCp 9细胞对GI MC组织密度的贡献。 关于预期结果，目标I中提出的研究预期将定义鼠和 人MCp 9祖先和功能性; 2）确定在人MCp 9基因表达中连续的TGF β 1和IL-33信号的参与。 IL 9 CNS 25元件在MCp 9形成中的调节，和3）证明需要MCp 9衍生的IL- 9在食物过敏和定义这种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提供一个新的和实质性的出发点， 目前对食物过敏中GI MC密度的潜在分子机制的理解， 这种细胞在食物过敏中增加MC组织密度的需要，从而指导 用于治疗食物过敏和过敏反应的新的和现有的治疗剂。