Neuroimmune Control of Allergic Immunity

过敏性免疫的神经免疫控制

• 批准号: 10211590
• 负责人: Caroline Lauren Sokol
• 金额: $ 59.63万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211590
• 关键词: Address; Afferent Neurons; Allergens; Allergic; Allergic Disease; Antigens; B-Lymphocytes; Bacteria; Basophils; CCR8 gene; Cell Maturation; Cell physiology; Cells; Cellular Immunology; Cellular Neurobiology; Cutaneous; Data; Dendritic Cells; Dendritic cell activation; Dermal; Dermis; Detection; Development; Disease; Foundations; Goals; Health; IgE; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; In Vitro; Innate Immune System; Interleukin-4; Laboratories; Licensing; Lymphoid Cell; Mus; Nervous system structure; Neuroimmune; Neurons; Neuropeptides; Papain; Papaya; Pathway interactions; Patients; Peptide Hydrolases; Play; Population; Prevalence; Production; Pruritus; Research; Role; Sensory; Signal Transduction; Skin; Substance P; T-Lymphocyte; TRPV1 gene; Testing; Th2 Cells; United States; Venoms; adaptive immune response; base; cell motility; chronic itch; draining lymph node; environmental allergen; experience; fungus; immune activation; improved; in vivo; insight; mast cell; migration; neurotransmitter release; novel; novel therapeutic intervention; novel therapeutics; pain sensation; prevent; programs; release factor; response; sensor; therapeutic development; tool

Project Summary/Abstract One central paradox in the initiation of allergic immunity is that although dendritic cells are necessary for the initiation of allergic immune responses, dendritic cells are activated in vivo by allergen immunization, but not directly in vitro by allergens. This indicates that another cell may act upstream of dendritic cells to act as the initial allergen sensor. Our long-term goal is to understand how the innate immune system is activated by allergens to initiate the allergic immune response. Given that 40% of the United States population suffers from one or more allergic diseases and that the prevalence of allergic disease continues to increase worldwide, we believe there is an urgent health need to understand how allergic diseases are initiated. We recently found that sensory neurons are directly activated by allergens in vivo and in vitro, leading to the release of Substance P that activates the migration of Th2-skewing dendritic cells through their expression of MRPGPRA1. Our central hypothesis is that sensory neurons are the initial sensors of allergens and that their interactions with innate immune cells both promote sensory neuronal responsiveness to allergens and allows sensory neurons to initiate the allergic immune response. Building upon recent breakthroughs detailing sensory neurons involved in allergen sensing, dendritic cell subsets that respond to allergens, and mechanisms of allergic-skewing dendritic cell migration, we propose to integrate tools of cellular immunology and neurobiology to gain a fundamental understanding of neuroimmune interactions that promote allergic immune activation. Using these tools, we propose to test our central hypothesis in two specific aims: (1) determine the mechanisms by which allergen-stimulated sensory neurons interact with and initiate dendritic cell activation, and (2) identify how  T cells control sensory neuron activation by allergens. Aim 1 will examine the interactions between sensory neurons and dendritic cells, and the requirement for Substance P and MRGPRA1 in these interactions. Aim 2 will address how a novel subset of dermal  T cells may endow or promote the responsiveness of sensory neurons to allergens. These studies will lay the groundwork for the development of therapeutic strategies to prevent initial allergic sensitization (Aim 1), treat chronic itch diseases (Aim 2), and prevent polysensitization in patients with pre-existing allergic disease (Aims 1 & 2).

项目概要/摘要 过敏性免疫启动过程中的一个中心悖论是，尽管树突状细胞是过敏性免疫启动所必需的， 过敏性免疫反应的启动，树突状细胞在体内被过敏原免疫激活，但不是 直接在体外受到过敏原的影响。这表明另一个细胞可能在树突状细胞的上游发挥作用 初始过敏原传感器。我们的长期目标是了解先天免疫系统是如何被激活的 过敏原启动过敏免疫反应。鉴于 40% 的美国人口患有 一种或多种过敏性疾病，并且过敏性疾病的患病率在全球范围内持续增加，我们 相信健康方面迫切需要了解过敏性疾病是如何引发的。我们最近发现 感觉神经元在体内和体外被过敏原直接激活，导致 P 物质的释放 通过 MRPGPRA1 的表达激活 Th2 倾斜树突状细胞的迁移。我们的中央 假设是感觉神经元是过敏原的初始传感器，并且它们与先天的相互作用 免疫细胞既促进感觉神经元对过敏原的反应，又允许感觉神经元 启动过敏性免疫反应。以最近详细描述所涉及的感觉神经元的突破为基础 在过敏原传感、对过敏原做出反应的树突状细胞亚群以及过敏偏向机制中 树突状细胞迁移，我们建议整合细胞免疫学和神经生物学的工具来获得 对促进过敏性免疫激活的神经免疫相互作用的基本了解。使用这些 工具，我们建议在两个具体目标中检验我们的中心假设：（1）确定机制 过敏原刺激的感觉神经元与树突状细胞相互作用并启动树突状细胞激活，(2) 确定如何  T 细胞通过过敏原控制感觉神经元的激活。目标 1 将检查感官之间的相互作用 神经元和树突状细胞，以及这些相互作用中对 P 物质和 MRGPRA1 的需求。目标2 将解决真皮  T 细胞的新子集如何赋予或促进感觉反应能力 神经元对过敏原。这些研究将为制定治疗策略奠定基础 预防初始过敏（目标 1），治疗慢性瘙痒性疾病（目标 2），并预防多敏反应 已有过敏性疾病的患者（目标 1 和 2）。