Neuroimmune Control of Allergic Immunity

过敏性免疫的神经免疫控制

基本信息

批准号：
10823390
负责人：
Caroline Lauren Sokol
金额：
$ 9.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10823390
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

项目摘要

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，但不是这表明另一种细胞可能在树突状细胞的上游发挥作用。我们的长期目标是了解先天免疫系统是如何被激活的。鉴于 40% 的美国人口患有过敏原，从而引发过敏性免疫反应。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，我们我们最近发现，我们迫切需要了解过敏性疾病是如何引发的。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 偏向树突状细胞的迁移。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基于最近详细描述的感觉神经元的突破。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。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，并且（2）确定 T如何细胞通过过敏原控制感觉神经元的激活。目标 1 将检查感觉神经元之间的相互作用。神经元和树突状细胞，以及这些相互作用中 P 物质和 MRGPRA1 的需求。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这些研究将为开发针对过敏原的治疗策略奠定基础。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）。