Initiation of Contact and Asthmatic Hypersensitivity

接触的开始和哮喘过敏

• 批准号: 7023890
• 负责人: PHILIP William ASKENASE
• 金额: $ 35.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023890
• 关键词: B lymphocyte; T lymphocyte; asthma; biological signal transduction; cell mediated cytotoxicity; cell migration; cell proliferation; cellular immunity; complement; complement pathway; contact dermatitis; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; genetically modified animals; glycolipids; haptens; histology; hypersensitivity; immune response; immunoglobulin M; interleukin 4; laboratory mouse; leukocyte activation /transformation; natural killer cells; occupational disease /disorder; pathologic process; skin hypersensitivity

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）：我们将在体内研究T细胞介导的免疫激发的“起始”。我们发现，引发是由于一系列的过程。我们假设这些过程在致敏后几小时内开始。我们假设在免疫后1小时内，存在Valpha 14 + Jalpha 18 + CD 1d限制性NKT细胞的活化。NKT细胞产生IL-4以共激活β-1 β细胞亚群以产生起始IgM抗体。这通过肥大细胞的局部补体C5 a活化导致效应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鼠模型中，以及在免疫后1天内涉及半抗原诱发气道高反应性（AHR）的职业性哮喘的相关模型中。类似地，假定AHR依赖于由NKT细胞刺激的β-1细胞介导的C5 a生成介导的早期过程。我们在这个建议中的重点是诱导CS起始β-1细胞。我们认为这是由于NKT细胞在接触免疫后数小时内快速活化，可能通过释放内源性糖脂抗原产生IL-4，IL-4共活化β-1细胞，产生起始IgM抗体。总之，这些研究将CS启动的研究扩展到介导β-1细胞的诱导，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细胞是否在CS中是必不可少的，它们是如何被激活的，以及NKT细胞是否通过潜在地产生IL-4而在CS的起始中起作用。 具体目标#2：我们将确定β-1细胞是否以及如何在CS诱导早期被IL-4激活，以及通过STAT-6信号传导起作用的IL-4是否是必需的，以及β-1细胞如何可能迁移到淋巴结，然后仅在免疫后1天产生循环CS起始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IgM抗体介导C5 α依赖性气道高反应性（AHR）;仅在免疫后1天;以及诱导的AHR的机制。