The overall goal of this application is to evaluate and define the effects of the neurotransmitter and vasodilator calcitonin gene-related peptide (CGRP) on cutaneous immunologic function. This work is based on recent observations that Langerhans cells are anatomically associated with CGRP- containing epidermal axons and that CGRP regulates their function in vitro. A series of experiments will examine the relevance of CGRP to antigen presentation in vitro and immunologic responsiveness in vivo. Morphologic studies will be performed on human skin to analyze the anatomic relationship between CGRP-containing axons and Langerhans cells during the evolution of allergic contact dermatitis. The distribution and amount of CGRP present will be assessed at various timepoints. This will provide correlative evidence for a role for CGRP in regulating cutaneous hypersensitivity. Other experiments will verify that epidermis-derived CGRP is biologically active. To further define the relevance of innervation to cutaneous immune responses, areas of skin will be denervated surgically in mice and the ability of such denervated skin sites to support the induction or elicitation of contact hypersensitivity will be examined. In vitro studies will be performed to further define the actions of CGRP. These will focus on the ability of CGRP to modulate antigen presentation, adhesion molecule expression, and cytokine release. Other experiments will attempt to determine whether CGRP induces macrophage or Langerhans cells to provide a tolerogenic signal rather than an immunogenic signal. To determine if exogenously administered CGRP can modify immune responses, the ability of mice to support the induction or elicitation of contact hypersensitivity after local or systemic administration of CGRP will be examined. The studies proposed herein will define an important locus of interaction between the nervous system and the immune system. Therefore, the results obtained will provide a greater understanding of how neurologic and psychologic status may influence immune function in the skin. Furthermore, such findings may lead to currently unforeseen new therapeutic approaches to treat immunologic derangements.
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