Neuroimmune Control of Allergic Immunity

过敏性免疫的神经免疫控制

• 批准号: 10625256
• 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/10625256
• 关键词: Afferent Neurons; Allergens; Allergic; Allergic Disease; Antigens; B-Lymphocytes; Bacteria; Basophils; CCR8 gene; Cell Communication; Cell Maturation; Cell physiology; Cells; Cellular Immunology; Cellular Neurobiology; Cutaneous; Data; Dendritic Cells; Dendritic cell activation; Dermal; Dermis; Detection; Development; Disease; Endowment; Foundations; Goals; Health; IgE; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; In Vitro; Innate Immune Response; Innate Immune System; Interleukin-4; Laboratories; Licensing; Lymphoid Cell; Mus; Nervous System; 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; 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).

项目总结/摘要 在过敏性免疫的启动过程中，一个中心矛盾是，尽管树突状细胞是过敏性免疫所必需的， 在过敏性免疫应答的启动中，树突状细胞通过过敏原免疫在体内被激活，但不 直接在体外通过过敏原。这表明另一种细胞可能在树突状细胞的上游起作用， 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。 过敏原引发过敏性免疫反应。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， 相信有一个迫切的健康需要了解过敏性疾病是如何开始的。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MRPGPRA 1的表达激活Th 2倾向性树突状细胞的迁移。我们的中央 一种假说认为，感觉神经元是过敏原的最初感受器， 免疫细胞既促进感觉神经元对过敏原的反应， 引发过敏性免疫反应基于最近的突破，详细说明了感觉神经元参与 在过敏原感应，树突状细胞亚群，过敏反应，和过敏偏斜的机制 树突状细胞迁移，我们建议整合细胞免疫学和神经生物学的工具， 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，我们建议在两个具体目标中测试我们的中心假设：（1）确定 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，以及（2）确定树突状细胞如何激活树突状细胞。 细胞通过过敏原控制感觉神经元的激活。目标1将研究感官之间的相互作用 神经元和树突状细胞，以及在这些相互作用中对P物质和MRGPRA 1的需求。目的2 将解决如何一个新的亚群真皮淋巴细胞T细胞可能赋予或促进反应的感觉 神经元过敏原。这些研究将为开发治疗策略奠定基础， 预防初始过敏性致敏（目标1），治疗慢性瘙痒性疾病（目标2），预防 患有既存过敏性疾病的患者（目的1和2）。