REGULATION OF LANGERHANS CELL FUNCTION

本申请的长期目标是进一步了解 调节表皮内的抗原呈递。 这个过程 不仅对于识别进入的病原体非常重要， 皮肤有效的免疫反应，但也因为 抗原呈递在免疫识别中的假定作用 早期皮肤恶性肿瘤 紫外线辐射引起的皮肤癌，至少 在小鼠中具有免疫原性，并在移植后退化， 同基因受体。 特异性免疫变化发生在 主要宿主作为UVR暴露的结果， 免疫介导的肿瘤破坏，并导致 宽容 使用对半抗原的接触超敏反应的研究， 对同种异体抗原的迟发型超敏反应已经证明， UVR暴露后某些细胞因子的释放起作用， 紫外线辐射引起的免疫抑制 两者都有证据 DNA和尿刊酸（UCA）作为皮肤中的发色团， 一系列事件导致照射后免疫抑制。 的 特别感兴趣的是树突状表皮抗原呈递细胞 （朗格汉斯细胞，LC）能够呈递肿瘤相关的免疫球蛋白。 抗原（TAA）诱导和引发肿瘤特异性 免疫力和这一过程是由许多细胞因子， 包括GM-CSF、TNF-α和IL-10。 因此 LC的微环境（在皮肤或引流淋巴结中） 可能决定LC对初始T细胞的有效性 或者刺激记忆T细胞被激活。 假设， 可以测试的是，表皮抗原呈递，包括呈递 对于肿瘤的免疫应答，由某些细胞因子调节， 包括在UVR暴露后由角质形成细胞产生的那些，以及 如顺式-UCA。 多种细胞因子在LC中的相互作用 呈现功能将被检查，因为存在多个 细胞因子可能在原位。 特异性细胞因子在免疫中的作用 将通过使用基因靶向的， 精氨酸缺乏小鼠。 由于IL-10是UVR的重要介质， 诱导免疫抑制，转基因小鼠过表达IL-10， 将产生表皮以检查它们的免疫能力。 此外，涉及长期暴露于 UVR将使用精氨酸缺陷（或受体缺陷） 和转基因小鼠，以检查特定细胞因子在UVR中的作用， 诱发癌 总的来说，本文提出的研究将 大大扩展了对免疫生物学的理解， 表皮及其与UVR效应的关系，包括诱导 皮肤癌

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.