Phenolic compounds, natural or synthetic, are ubiquitous in man's environment. Phenols have complicated effects on biological systems. For example, phenols with nucleophilic side chains in the para position (parasubstituted phenols -- PSP) applied topically to the skin induce proliferation of keratinocytes and pigment cells. PSP markedly alter the numerical density of Ia positive epidermal Langerhans cell populations, i.e., increase or decrease their number depending on the dose of PSP applied. Langerhans cells (LC) are immune macrophages in the epidermis. Their surface Ia markers seem essential for their interaction with T-lymphocytes and for initiation of immune reactivity. Alterations in Ia positive cells by PSP probably will alter cutaneous immune reactivity. From other work completed, we suggest one mechanism by which PSP alter LC is by initiating the oxidation of arachidonic acid to prostaglandins and/or leukotrienes. The objective of this proposal is to study the effects of PSP and prostaglandins on cutaneous immune reactivity in vitro and in vivo. Commonly available compounds like 4-hydroxy anisole and monobenzyl ether of hydroquinone will be applied to the skin of mice. Tissue will be stained by Ia fluorescent antibody or ATPase enzymic techniques, and alterations in the number and morphology of LC determined. Animals with excessive or depleted LC will be contact sensitized to DNFB to determine whether these agents alter immune reactivity. Skin of animals known to be sensitive to DNFB will be depleted of Ia positive LC and challenged to the antigen in order to determine whether LC have a role in the efferent cutaneous inflammatory response. Epidermis with augmented or depleted numbers of LC will be made into single cell suspensions. The ability of LC in these suspensions to present antigen to syngeneic or allogeneic T-cells, to activate allogeneic T-lymphocytes (MLR) will be measured by in vitro techniques such as the uptake of tritiated thymidine. In prior studies, we have documented that PSP induce oxidation of arachidonic acid to prostaglandins and leukotrienes by epidermal sheets. Prostaglandin-D and thromboxane are the two major products. They may have slightly altered structures from similar compounds previously isolated. We will perform a series of studies to determine the effects of prostaglandins, thromboxanes, and leukotrienes on the function of Langerhans cells in vitro and in vivo.
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