Initiation of Contact and Asthmatic Hypersensitivity

接触的开始和哮喘过敏

• 批准号: 7183609
• 负责人: PHILIP William ASKENASE
• 金额: $ 34.88万
• 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/7183609
• 关键词: Initiation; Contact; Asthmatic; 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(申请人提供)：我们将在体内研究T细胞介导的免疫诱导的“启动”。我们发现，启发式的启动是一系列过程的结果。我们假设这些过程在致敏后数小时内开始。我们推测，在免疫后1小时内，存在Valpha14+Jalpha18+CD1d限制性NKT细胞的激活。NKT细胞产生IL-4，共同激活Beta-1 Beta细胞亚群，产生启动的IgM抗体。这导致通过局部补体C5a激活肥大细胞，使效应性T细胞局部募集到抗原攻击部位。这些启动过程发生在过敏性接触性皮炎的小鼠模型中，以及在免疫后1天内涉及呼吸道高反应性(AHR)半抗原诱导的相关职业性哮喘模型中。AHR类似地被认为依赖于由NKT细胞刺激的Beta-1细胞介导的C5a产生所介导的早期过程。我们在这个方案中的重点是诱导CS启动的Beta-1细胞。我们认为这是由于NKT细胞先前的快速激活，可能是通过在接触免疫后几个小时内释放内源性糖脂抗原来产生IL-4，从而共同激活Beta-1细胞，从而产生起始的IgM抗体。综上所述，这些研究将CS启动的研究扩展到诱导可能通过NKT细胞IL-4激活的介导性Beta-1细胞，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在CS的启动中发挥作用。 具体目标2：我们将确定在CS诱导早期，IL-4是否以及如何激活Beta-1细胞，IL-4是否通过STAT-6信号起作用，以及Beta-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启动的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B-1细胞衍生的IgM抗体的产生中的潜在作用，该抗体介导C5a依赖的气道高反应性(AHR)；免疫后仅1天；以及诱导AHR的机制。