REGULATION OF LANGERHANS CELL FUNCTION

朗格汉斯细胞功能的调节

• 批准号: 6055626
• 负责人: RICHARD David GRANSTEIN
• 金额: $ 25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-20 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6055626
• 关键词: Langerhans' cell; cellular immunity; contact dermatitis; cytokine; delayed hypersensitivity; genetically modified animals; interleukin 10; keratinocyte; laboratory mouse; light adverse effect; neoplasm /cancer immunology; radiation carcinogenesis; skin neoplasms; ultraviolet radiation; urocanate

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.

本应用程序的长期目标是进一步了解 调节表皮内的抗原提呈。这一过程 非常重要，不仅对于识别进入的病原体 对于皮肤的有效免疫反应，也是因为 抗原提呈在免疫识别中的作用 早期的皮肤恶性肿瘤。至少是紫外线辐射诱发的皮肤癌 在小鼠中，是免疫原性的，并在移植到 同基因受者。特定的免疫学变化发生在 作为紫外线照射的主要宿主，防止 免疫介导的肿瘤破坏并导致一种状态 宽容。利用接触性超敏反应对半抗原和 对同种异体抗原的迟发性超敏反应已经证明 紫外线照射后某些细胞因子的释放起着一定的作用 在紫外线诱导的免疫抑制中。两种情况都有证据 DNA和尿毒酸(UCA)作为皮肤中的生色团，启动了 照射后导致免疫抑制的一系列事件。的 特别感兴趣的是树突状表皮抗原提呈细胞 (朗格汉斯细胞，LC)能够呈现与肿瘤相关的 诱导和诱导肿瘤特异性抗原(TAA) 免疫，这一过程受许多细胞因子的调节， 包括粒细胞集落刺激因子、肿瘤坏死因子-α和白介素10。因此， ，LC的微环境(在皮肤或引流淋巴结内) 可能会关键地决定LC对初始T细胞的激活效果 或者刺激记忆T细胞被激活。假设是为了 被检测的是表皮抗原提呈，包括提呈 对于肿瘤的免疫反应，受某些细胞因子的调节， 也包括紫外线照射后角质形成细胞产生的那些 就像顺-UCA一样。多种细胞因子在LC中的相互作用 将检查演示功能，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 反应将通过使用基因靶向， 细胞因子缺陷小鼠。由于Il-10是UVR的重要调解人- 诱导免疫抑制，转基因小鼠过表达IL-10 将创建表皮来检查它们的免疫能力。 此外，涉及慢性接触的致癌研究 UVR将使用细胞因子缺陷(或受体缺陷)进行治疗 和转基因小鼠，以检测特定细胞因子在紫外线照射中的作用 诱导致癌。作为一个整体，这里提出的研究将 大大扩展了对猪的免疫生物学的了解 表皮及其与UVR效应的关系 皮肤癌。

项目成果

Altered cutaneous immune parameters in transgenic mice overexpressing viral IL-10 in the epidermis.

• DOI: 10.1172/jci15722
• 发表时间: 2003-06
• 期刊: The Journal of clinical investigation
• 作者: W. Ding;S. Beissert;L. Deng;E. Miranda;Christopher T Cassetty;K. Seiffert;K. Campton;Zhengming Yan;G. Murphy;J. Bluestone;R. Granstein