Initiation of Contact and Asthmatic Hypersensitivity

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 中是否至关重要、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，以及通过 STAT-6 信号传导起作用的 IL-4 是否是必需的，以及 Beta-1 细胞如何可能迁移到淋巴结，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。

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.