ALLERGIC CONTACT DERMATITIS: MECHANISMS OF ELICITATION

描述(由申请人提供)： 过敏性接触性皮炎是一种T细胞介导的皮肤炎症性疾病，由皮肤表面暴露于反应性半抗原引起。这是一种常见的人类经验；对有毒常春藤的反应剂漆酚的炎症反应就是这样的一个例子。在小鼠中，已经确定了几种方法，如果在初始致敏之前应用(即抗原特异性耐受)，将抑制对接触性变应原的免疫反应。然而，在已经致敏(脱敏)的动物中，抗原特异性下调变态反应性接触性皮炎的作用一直难以实现，这仍然是接触性超敏研究中的主要挑战之一。我们最近的研究表明，B7H1可以灭活变应原特异性T细胞的功能，并可以抑制已经致敏的小鼠诱发变态反应性接触性皮炎。B7H1是表达在变应原激活的T细胞上的抑制分子PD-1的配体。B7H1与PD-1相互作用可抑制T细胞增殖，诱导T细胞凋亡。在这项建议中，我们假设B7H1共刺激可以灭活变应原特异性T细胞，并介导变态反应性接触性皮炎的耐受和脱敏。为了检验这一假设，本文提出了四个具体目标。(1)探讨B7H1在接触性变应原特异性T细胞形成中的作用。(2)评估B7H1阳性树突状细胞和/或角质形成细胞是否能有效地诱导已经对接触性变应原致敏的小鼠脱敏。(3)确定B7H1抑制变应原特异性T细胞功能的机制是由于变应原特异性T细胞的耗竭、无能或抑制。(4)确定抑制T细胞功能的B7H1配体。在基础水平上，该结果将提供关于B7H1共刺激在诱导和激发免疫反应中的作用的关键信息，并将增加关于B7H1的特定配体调节激活的T细胞的细胞因子的产生、增殖和凋亡的机制的新信息。在临床层面上，该提案的结果可能导致针对变态反应性接触性皮炎患者的抗原特异性脱敏的免疫治疗方法的开发。

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.