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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：
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
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/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

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).

项目总结/文摘