The research in this proposal is designed to utilize hapten specific T-cell hybridomas to investigate the development and regulation of contact hypersensitivity in mice. These objectives will be achieved by investigating 1. the immune response to topically applied haptens and 2. the effects of ultraviolet B irradiation and phorbol esters on the immunologic functions of the skin. We have made T-cell hybridomas that are specific for fluorescein isothiocyanate or trinitrophenol coupled antigen presenting cells (APCs). These hybridomas will be used to study: a. the identify of the nominal antigens(hapten plus protein) that are responsible for the induction of contact hypersensitivity; b. T-cell receptor gene usage in the immune response to topically applied haptens; and c. characteristics of hapten bearing APCs that appear in the epidermis, dermis, and other regional lymph nodes of sensitized mice. We intend to make T-cell hybridomas in other strains of mice (C57BL/10 and C3H.HEJ) that will allow us to study the development of contact hypersensitivity in strains of mice that are known to have different reactivity to contact allergens and different responses to local UVB irradiation. To assess the effects of UVB and phorbol myristate acetate (PMA) on the immunologic functions of the skin, we intend to use hapten specific hybridomas to determine whether: a. treatment of mice locally with low dose UVB irradiation or with PMA affects the appearance and functional capacity of APCs in the epidermis, dermis and regional lymph nodes; b. the effects of UVB or PMA can be produced by lymphokines (eg. gamma-interferon [gamma- IF] or tumor necrosis factor alpha [TNFalpha]) or can be blocked by antibodies directed against lymphokines (eg. gamma-IF or TNFalpha); c. strain differences in sensitivity to low dose, local UVB treatment; d. hapten coupled APCs which are treated with low dose UVB in vitro are capable of stimulating hapten-specific hybridomas; and APC function can be restored with lymphokines (eg. IL-1) if defects in the ability of UVB treated APCs to stimulate the hybridomas are detected. These investigations will broaden our understanding of the role of the skin as a component of the immune system and may have a significant impact on our ideas about the therapy and prevention of immune mediated diseases of the skin.
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