Differential regulation of mast cell-mediated allergic responses by IL-10

IL-10 对肥大细胞介导的过敏反应的差异调节

• 批准号: 10584859
• 负责人: Clinton B Mathias
• 金额: $ 40.28万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584859
• 关键词: Adoptive Transfer; Allergens; Allergic; Allergic inflammation; Anaphylaxis; Antiinflammatory Effect; Antiparasitic Agents; Attenuated; Automobile Driving; Bone Marrow; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Line; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Chymase; Connective Tissue; Data; Development; Disease; Enhancers; Event; Exhibits; Food Hypersensitivity; Goals; Heterogeneity; Homeostasis; Human; Hypersensitivity; IgE; Immune; Immune response; Immunodeficient Mouse; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-6; Interleukin-9; Intestines; Investigation; Light; Maps; Mediating; Mission; Modeling; Mucous Membrane; Mus; National Institute of Allergy and Infectious Disease; Nature; Outcome; Pathologic; Pathway interactions; Peritoneal; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Production; Proliferating; Reaction; Regulation; Regulatory T-Lymphocyte; Reporting; Rheumatoid Arthritis; Role; Shapes; Signal Pathway; Signal Transduction; Skin Tissue; Source; Stem Cell Factor; Stimulus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; allergic response; autocrine; cell behavior; cell mediated immune response; cell type; conditioning; cytokine; egg; food allergen; food antigen; immunoregulation; insight; mast cell; mastocytosis; novel; paracrine; prototype; receptor; response; transcriptomics; tumor-immune system interactions

PROJECT SUMMARY This project focuses on the mechanisms by which IL-10 differentially regulates and promotes mast cell (MC) hyperplasia, heterogeneity, activation and cellular functions during the development of IgE and non-IgE-mediated allergic responses to food antigens. We have demonstrated a key role for the immunomodulatory cytokine IL-10 in driving MC expansion, activation, and cytokine production during food allergy. IL-10-primed MCs exhibited enhanced proliferation, IgE-mediated passive anaphylaxis, and the production of TH2-type cytokines. This suggests a novel role for IL-10 in the homeostasis and function of MCs. However, the mechanisms by which IL-10 promotes MC activation are not very clear and remain to be determined. Furthermore, whether these proinflammatory effects of IL-10 on MCs extend to specific MC lineages, are global in nature, or context-dependent also remain to be examined. This project combines hypothesis testing and targeted mechanistic approaches to further probe the mechanisms by which IL-10 regulates MC functions. These include understanding whether IL-10 differentially regulates MC responses to distinct antigenic stimuli, assessment of its effects on heterogeneous MC subsets, and determination of whether its effects are controlled by the source cell type. The long-term overall goals are to: 1) identify cell-intrinsic and extrinsic factors by which IL-10 promotes or suppresses distinct MC populations and regulates their effector function during type 2 inflammatory responses; and 2) examine the systemic and functional local tissue consequences of regulation of MC expansion and activation by IL-10. Aim 1 will elucidate whether IL-10 promotes IgE-mediated mucosal MC responses to physiological food antigens such as peanut and egg allergen and examine its effects on non-IgE-mediated pathways of allergic sensitization including IL-33-induced anaphylaxis. Whether the effects of IL-10 also extend to connective tissue MCs will be assessed and the phenotypic and transcriptomic profiles of both MC subsets will be mapped. Aim 2 will assess the contributions of cell-intrinsic and paracrine IL- 10 to MC hyperplasia and effector function. Aim 3 will identify the effects of source-dependent IL- 10 and determine whether TH2 or non-TH2-derived IL-10 can differentially regulate MC function. Given the known pleiotropic pathologic and regulatory effects of IL-10 during various T and MC- mediated immune responses including anti-parasitic responses and allergy, and considering its status as a canonical immunoregulatory cytokine, it is important to further identify the mechanisms underlying the proinflammatory effects of IL-10 and its ability to promote rather than suppress MC-dependent responses. As such, these studies are not only relevant to the mission of NIAID but may also serve to identify precision-based approaches for therapeutic interventions.

项目摘要 该项目侧重于IL-10差异调节和促进的机制 肥大细胞（MC）增生，异质性，激活和细胞功能 对食品抗原的IgE和非IgE介导的过敏反应的发展。 我们已经证明了免疫调节细胞因子IL-10在驱动MC中的关键作用 食物过敏期间的膨胀，激活和细胞因子产生。 IL-10推出的MCS展出 增强的增殖，IgE介导的被动过敏反应和Th2型的产生 细胞因子。这表明IL-10在MC的稳态和功能中起了新的作用。然而， IL-10促进MC激活的机制不是很清楚，并且保持不变 决定。此外，IL-10对MC的这些促炎作用是否扩展到 特定的MC谱系本质上是全球性的，或者与上下文有关的依赖性也有待研究。这 项目结合了假设检验和针对性的机械方法，以进一步探测 IL-10调节MC功能的机制。其中包括了解IL-10是否 差异调节MC对不同抗原刺激的反应，评估其对 异质MC子集，并确定其效应是否由源控制 细胞类型。长期总体目标是：1）通过 IL-10促进或抑制不同的MC种群并调节其效应子功能 在2型炎症反应中； 2）检查全身和功能性的局部组织 IL-10调节MC扩展和激活的后果。 AIM 1将阐明是否 IL-10促进了IgE介导的粘膜MC对生理食品抗原的反应，例如 花生和卵子过敏原检查其对过敏性非IGE介导的途径的影响 敏化，包括IL-33诱导的过敏反应。 IL-10的影响是否也扩展到 将评估结缔组织MC，并将两者的表型和转录谱。 MC子集将被映射。 AIM 2将评估细胞内和旁分泌IL-的贡献 10到MC增生和效应函数。 AIM 3将确定依赖源的IL-的影响 10并确定TH2或非TH2衍生的IL-10是否可以差异调节MC函数。 鉴于IL-10在各种T和MC-中的已知多效性病理和调节作用 介导的免疫反应，包括抗寄生虫反应和过敏，并考虑其 作为规范免疫调节细胞因子的状态，进一步识别机制很重要 IL-10及其促进的能力而不是抑制的基础 依赖MC的响应。因此，这些研究不仅与Niaid的使命有关 但也可能有助于确定基于精确的治疗干预方法。