ALLERGIC CONTACT DERMATITIS: MECHANISMS OF ELICITATION

点击翻译按钮获取中文摘要

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.