Initiation of Contact and Asthmatic Hypersensitivity

接触的开始和哮喘过敏

基本信息

批准号：
7367191
负责人：
PHILIP William ASKENASE
金额：
$ 34.22万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367191
关键词：
Accounting Adult asthma Allergens Allergic Allergic Contact Dermatitis Animals Antibodies Antibody Formation Antigens Applications Grants Area Asthma Autoimmunity B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Beta Cell Binding C5a anaphylatoxin receptor Cell physiology Cells Cellular Immunity Centers for Disease Control and Prevention (U.S.)Complement Complement 5a Contact Dermatitis Cutaneous Delayed Hypersensitivity Development Disease Environment Event Generations Glycolipids Haptens Health Home environment Hour Human Hypersensitivity Immune Immune response Immunity Immunization Immunoglobulin M Immunologics Immunology Infection Inflammation Inflammatory Interleukin-4 Isocyanates Lead Ligands Limb structure Link Lung diseases Mediating Mediator of activation protein Modeling Mus Natural Immunity Numbers Occupational Occupational Asthma Occupational Dermatitis Occupational Diseases Occupational Medicine Participant Prevention Process Production Property Reaction Recruitment Activity Research Personnel Role Series Signal Transduction Site Skin Steroids T-Lymphocyte Testing Therapeutic Intervention Time Week Work Workplace acquired immunity airway hyperresponsiveness antigen challenge asthmatic airway base concept day environmental health economics in vivo in vivo Model lymph nodes mast cell mouse model programs research study response statistics tumor

项目摘要

DESCRIPTION (provided by applicant): We will study the "initiation" of the elicitation of T cell mediated immunity in vivo. We have discovered that the initiation of elicitation is due to a series of processes. We postulate that these processes begin within hours after sensitization. We postulate that within 1-hr of immunization there is activation of Valpha14+ Jalpha18+ CD1d-restricted NKT cells. The NKT cells produce IL-4 to co-activate the Beta-1 Beta cell subset to produce initiating IgM antibodies. This, leads via local complement C5a activation of mast cells, to the local recruitment of effector T cells to the site of Ag challenge. These initiating processes occur in the murine model of allergic contact dermatitis, and in a related model of occupational asthma involving hapten elicitation of airway hyperreactivity (AHR) within 1-day of immunization. AHR similarly is postulated to depend on an early process mediated by NKT cell stimulated Beta-1 cell mediated C5a generation. Our focus in this proposal is the induction of CS-initiating Beta-1 cells. We propose this is due to prior rapid activation of NKT cells, perhaps via release endogenous glycolipid antigens, within hours post-contact immunization, to produce IL-4 that co-activates the Beta-1 cell, to produce the initiating IgM antibodies. Taken together, these studies extend the study of CS-initiation to induction of the mediating Beta-1 cells, potentially activated via NKT cell IL-4, and extend these concepts to mouse models of occupational medicine. Specific Aim #1: We will determine whether NKT cells are essential in CS, how they are activated, and if the NKT cells function in the initiation of CS by potentially producing IL-4. Specific Aim #2: We will determine if and how Beta-1 cells are activated by IL-4 early in the induction of CS, and whether IL-4, acting via STAT-6 signaling is essential, and how the Beta-1 cells may possibly migrate to lymph nodes and then to produce circulating CS-initiating IgM antibodies by only 1-day post-immunization. Specific Aim #3: In a hapten induced murine model of occupational asthma, we will determine the potential role of NKT cells in the production of B-1 cell derived IgM antibodies, that mediate C5a-dependent airway hyperreactivity (AHR); just 1-day post-immunization; and the mechanisms of the induced AHR.

描述（由申请人提供）：我们将研究体内 T 细胞介导的免疫引发的“启动”。我们发现诱导的启动是由一系列过程引起的。我们假设这些过程在致敏后数小时内开始。我们假设在免疫后 1 小时内，Valpha14+ Jalpha18+ CD1d 限制性 NKT 细胞被激活。 NKT 细胞产生 IL-4，共同激活 Beta-1 Beta 细胞亚群，产生起始 IgM 抗体。这通过肥大细胞的局部补体 C5a 激活，导致效应 T 细胞局部募集到 Ag 攻击位点。这些起始过程发生在过敏性接触性皮炎的小鼠模型中，以及涉及半抗原在免疫后 1 天内引发气道高反应性 (AHR) 的相关职业性哮喘模型中。类似地，AHR 被假定依赖于由 NKT 细胞刺激的 Beta-1 细胞介导的 C5a 生成介导的早期过程。我们这项提案的重点是诱导 CS 启动 Beta-1 细胞。我们认为这是由于 NKT 细胞先前快速激活，可能是通过在接触免疫后数小时内释放内源糖脂抗原，产生共同激活 Beta-1 细胞的 IL-4，从而产生起始 IgM 抗体。总而言之，这些研究将 CS 启动的研究扩展到诱导介导的 Beta-1 细胞（可能通过 NKT 细胞 IL-4 激活），并将这些概念扩展到职业医学的小鼠模型。具体目标#1：我们将确定 NKT 细胞在 CS 中是否必不可少、它们如何被激活，以及 NKT 细胞是否通过潜在产生 IL-4 在 CS 启动中发挥作用。具体目标 #2：我们将确定在 CS 诱导早期，Beta-1 细胞是否以及如何被 IL-4 激活，通过 STAT-6 信号传导发挥作用的 IL-4 是否是必需的，以及 Beta-1 细胞如何被激活。可能会迁移到淋巴结，然后在免疫后仅 1 天产生循环 CS 启动 IgM 抗体。具体目标#3：在半抗原诱导的职业性哮喘小鼠模型中，我们将确定 NKT 细胞在产生 B-1 细胞衍生的 IgM 抗体中的潜在作用，该抗体介导 C5a 依赖性气道高反应性 (AHR)；免疫后仅 1 天；以及诱导 AHR 的机制。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functions of Exosomes and Microbial Extracellular Vesicles in Allergy and Contact and Delayed-Type Hypersensitivity.

DOI：
10.1159/000449249
发表时间：
2016
期刊：
International archives of allergy and immunology
影响因子：
2.8
作者：
Nazimek K;Bryniarski K;Askenase PW
通讯作者：
Askenase PW

Natural killer cell-mediated contact dermatitis-like reaction induced by treatment with TLR3 ligand poly(I:C).

TLR3 配体聚 (I:C) 治疗诱导自然杀伤细胞介导的接触性皮炎样反应。

DOI：
10.1111/cod.14380
发表时间：
2023
期刊：
Contact dermatitis
影响因子：
5.5
作者：
Majewska-Szczepanik,Monika;Kowalczyk,Paulina;Askenase,PhilipW;Szczepanik,Marian
通讯作者：
Szczepanik,Marian

Diagnostic and therapeutic potentials of exosomes in CNS diseases.