ALLERGIC CONTACT DERMATITIS: MECHANISMS OF ELICITATION

描述（由申请人提供）： 变应性接触性皮炎是一种T细胞介导的皮肤炎症性疾病，由皮肤接触反应性半抗原引起。这是一种常见的人类经历;对毒葛的反应剂漆酚的炎症反应就是这样一个例子。在小鼠中，已经确定了几种方法，如果在初始致敏之前应用，将抑制对接触性过敏原的免疫应答（即，e.抗原特异性耐受性）。然而，在已经致敏（脱敏）的动物中，抗原特异性下调变应性接触性皮炎已经很难实现，并且仍然是接触性超敏反应研究的主要挑战之一。我们最近的研究表明，B7 H1可以抑制过敏原特异性T细胞的功能，并可以减少已经致敏的小鼠变应性接触性皮炎的诱发。B7 H1是在过敏原活化的T细胞上表达的抑制性分子PD-1的配体。B7 H1与PD-1的相互作用可抑制T细胞的增殖并诱导其凋亡。在这个提议中，我们假设B7 H1共刺激可以刺激过敏原特异性T细胞，介导过敏性接触性皮炎的耐受和脱敏。为了检验这一假设，提出了四个具体目标。(1)研究B7 H1在接触性过敏原特异性T细胞发育中的作用。(2)评估B7 H1阳性树突状细胞和/或角质形成细胞是否能有效诱导已对接触性过敏原致敏的小鼠对接触性过敏原的脱敏。（3）确定B7 H1抑制过敏原特异性T细胞功能的机制是否是由于过敏原特异性T细胞的耗竭、无反应性或抑制。(4)鉴定负责抑制T细胞功能的B7 H1配体。在一个基本的水平上，这些结果将提供关键的信息B7 H1共刺激的作用，在诱导和引发免疫反应，并将增加新的信息的机制，通过该机制，B7 H1的特异性配体调节细胞因子的产生，增殖和活化的T细胞凋亡。在临床水平上，该提案的结果可能导致过敏性接触性皮炎患者抗原特异性脱敏的免疫学方法的发展。

DESCRIPTION (provided by applicant): Allergic contact dermatitis is a T-cell mediated cutaneous inflammatory disease caused by epicutaneous exposure to reactive haptens. It is a common human experience; the inflammatory reaction to urushiol, the reactive agent of poison ivy, is one such example. In mice several methods have been identified that will inhibit the immune response to contact allergens if applied prior to initial sensitization (i. e. antigen specific tolerance). However, antigen specific down-regulation of allergic contact dermatitis in animals that are already sensitized (desensitization) has been much harder to achieve and remains one of the major challenges in contact hypersensitivity research. Our recent studies indicate that B7H1 can inactivate the function of allergen specific T cells and can curtail elicitation of allergic contact dermatitis in mice that have already been sensitized. B7H1 is a ligand for the inhibitory molecule PD-1 expressed on allergen activated T cells. The interaction of B7H1 with PD-1 can inhibit proliferation and induce apoptosis of T cells. In this proposal, we hypothesize that B7H1 co-stimulation can inactivate allergen specific T cells and mediate both tolerance and desensitization of allergic contact dermatitis. To examine this hypothesis, four specific aims are proposed. (1) To examine the role of B7H1 in the development of contact allergen specific T cells. (2) To assess whether B7H1 positive dendritic cells and/or keratinocytes are effective at inducing desensitization to a contact allergen in mice that have already been sensitized to it. (3) To determine whether the mechanism by which B7H1 inhibits the function of allergen specific T cells is due to depletion, anergy or suppression of allergen specific T cells. (4) To identify the ligand for B7H1 that is responsible for inhibition of T-cell function. On a basic level, the results will provide critical information concerning the role of B7H1 co-stimulation in the induction and elicitation of immune responses and will add new information about the mechanism by which specific ligands for B7H1 regulate cytokine production, proliferation and apoptosis of activated T cells. On a clinical level, the outcome of the proposal may lead to development of immunotherapeutic approaches for antigen specific desensitization of allergic contact dermatitis patients.