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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).

项目摘要/摘要启动变态反应免疫的一个中心悖论是，尽管树突状细胞对于过敏免疫反应的启动，树突状细胞在体内被过敏原免疫激活，但不是由过敏原直接在体外产生。这表明，另一个细胞可能作用于树突状细胞的上游，起到最初的过敏原传感器。我们的长期目标是了解先天免疫系统是如何通过过敏原启动过敏性免疫反应。鉴于40%的美国人口患有一种或多种过敏性疾病，并且过敏性疾病的流行率在全球范围内继续增加，我们认为有迫切的健康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变应原直接激活，导致P物质的释放这通过其MRPGPRA1的表达激活了Th2偏斜树突状细胞的迁移。我们的中央假设感觉神经元是过敏原的初始感受器，它们与先天的免疫细胞既促进感觉神经元对变应原的反应性，又允许感觉神经元启动过敏免疫反应。在详细描述涉及的感觉神经元的最新突破的基础上在过敏原感知中，树突状细胞亚群对过敏原的反应，以及过敏偏斜的机制树突状细胞的迁移，我们建议结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有基本的了解。使用这些工具，我们建议在两个特定的目标中检验我们的中心假设：(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T是如何细胞通过变应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MRGPRA1的需求。目标2 将阐述一种新的真皮T细胞亚群如何赋予或促进感觉的反应性神经元对过敏原的反应。这些研究将为制定治疗策略奠定基础预防初始过敏反应(目标1)，治疗慢性瘙痒疾病(目标2)，预防多发性过敏反应既往有过敏性疾病的患者(目标1和2)。