Initiation of Contact and Asthmatic Hypersensitivity

描述（由申请人提供）：我们将在体内研究T细胞介导免疫的“起始”激发。我们已经发现，启发的启动是由于一系列的过程。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，存在Valpha14+ Jalpha18+ cd1 -限制性NKT细胞的活化。NKT细胞产生IL-4共激活β -1 β细胞亚群，产生初始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攻击部位。这些启动过程发生在过敏性接触性皮炎小鼠模型和相关的职业性哮喘模型中，涉及免疫1天内气道高反应性（AHR）的半抗原激发。AHR同样被认为依赖于由NKT细胞刺激的β -1细胞介导的C5a生成介导的早期过程。我们在这个提议的重点是诱导cs启动β -1细胞。我们认为这是由于NKT细胞在接触免疫后的数小时内，可能通过释放内源性糖脂抗原，提前快速激活，产生IL-4，共同激活β -1细胞，产生初始IgM抗体。综上所述，这些研究将cs起始的研究扩展到介导β -1细胞的诱导，这些细胞可能通过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中。

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.