The long-term goal of this application is to further understand the regulation of antigen presentation within the epidermis. This process is of great importance, not only for recognition of pathogens entering the skin for an effective immune response, but also because of a putative role for antigen presentation in immunologic recognition of incipient cutaneous malignancies. UVR-induced skin cancers, at least in mice, are immunogenic and regress upon transplantation to syngeneic recipients. Specific immunogic changes occur in the primary host as a consequence of UVR exposure that prevent the immune-mediated destruction of the tumor and lead to a state of tolerance. Studies using contact hypersensitivity to haptens and delayed-type hypersensitivity to alloantigens have demonstrated that release of certain cytokines subsequent to UVR exposure plays a role in UVR-induced immunosuppression. There is evidence for both DNA and urocanic acid (UCA) as chromophores in skin that initiate a series of events leading to immunosuppression after irradiation. Of particular interest, dendritic epidermal antigen presenting cells (Langerhans cells, LC) are capable of presenting tumor-associated antigens (TAA) for induction and elicitation of tumor-specific immunity and this process is regulated by a number of cytokines, including GM-CSF, TNF-alpha, and IL-10. Thus, the ,microenvironment of the LC (in the skin or in draining lymph nodes) may critically determine the effectiveness of LC to prime naive T cells or stimulate memory T cells to become activated. The hypothesis to be tested is that epidermal antigen presentation, including presentation for immune responses to tumors, is regulated by certain cytokines, including those produced by keratinocytes after UVR exposure, as well as by cis-UCA. The interactions of multiple cytokines on LC presenting function will be examined, since the presence of multiple cytokines is likely in situ. The role of specific cytokines in immune responses will be examined in vivo through the use of gene-targeted, cytokine-deficient mice. Since Il-10 is an important mediator of UVR- induced immunosuppression, transgenic mice overexpressing IL-10 in the epidermis will be created to examine their immune competence. Furthermore, carcinogenesis studies involving chronic exposure to UVR will be performed using cytokine-deficient (or receptor-deficient) and transgenic mice to examine the role of specific cytokines in UVR- induced carcinogenesis. As a whole, the studies proposed herein will greatly expend the understanding of the immunobiology of the epidermis and its relationship to UVR effects including induction of skin cancer.
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