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).

项目摘要/摘要 在过敏性免疫的倡议中，一个中心悖论是，尽管树突状细胞是必需的 过敏性免疫反应的启动，树突状细胞被过敏原免疫激活，但不是 过敏原直接在体外。这表明另一个细胞可以在树突状细胞上游起作用作为 初始过敏原传感器。我们的长期目标是了解先天免疫系统如何被 过敏原以启动过敏性免疫反应。考虑到40％的美国人口遭受 一种或多种过敏性疾病，过敏性疾病的患病率在全球范围内继续增加，我们 相信紧急健康需要了解如何发起过敏性疾病。我们最近发现 感觉神经元在体内和体外直接激活，导致物质释放 这通过其表达MRPGPRA1激活了Th2扭曲树突状细胞的迁移。我们的中心 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 免疫细胞既可以促进对过敏原的感觉神经元反应，又使感觉神经元能够 启动过敏性免疫反应。基于最近的突破，详细介绍了感官神经元 在过敏原感应中，对过敏原反应的树突状细胞子集和过敏性稳定的机制 树突状细胞迁移，我们建议整合细胞免疫学和神经生物学工具，以获得 对促进过敏性免疫激活的神经免疫相互作用的基本理解。使用这些 工具，我们建议以两个具体目的测试我们的中心假设：（1）确定其机制 过敏原刺激的感觉神经元与树突状细胞激活相互作用并启动，（2） 细胞控制过敏原的感觉神经元激活。 AIM 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物质P和MRGPRA1的需求。目标2 将解决真皮细胞的新型子集如何赋予或促进感觉的反应性 过敏原的神经元。这些研究将为制定治疗策略的发展奠定基础 防止初始过敏敏感性（AIM 1），治疗慢性瘙痒疾病（AIM 2），并防止在 患有过敏性疾病的患者（目标1和2）。