EPIDERMAL ANTIGEN-PRESENTING CELLS AND TUMOR IMMUNITY

在某些品系的小鼠中已经证明，当紫外线 紫外线辐射（UVR）用于诱导皮肤恶性肿瘤， 作为UVR的直接后果，动物中发生免疫学变化 暴露，这些免疫功能的改变有助于保护 肿瘤免疫破坏，并允许其生长。 已经 假设这可能是由于UVR引起的扰动， 朗格汉斯细胞（LC），防止肿瘤相关的表现 抗原（TAA）激活免疫效应机制， 允许通过某些非LC表皮元件呈递TAA，和/或 UVR改变的LC诱导免疫下调。 这 数据表明，LC暴露于UVR后， 在体外，小鼠的引发提供了致耐受性信号（如果施用 静脉内）而不是免疫原性信号。 此外，非LC，表皮 元件，包括Thy 1（+）树突状表皮细胞（EC）和 高密度：I-A+ EC，可提呈半抗原，下调免疫力 暴露于或不暴露于改变LC功能的剂量的UVR。 然而，在这方面， 缺乏LC在肿瘤免疫中作用的直接功能证据。 本文提出的实验将解决这个问题。 客观 这些研究之一是检查表皮抗原呈递的能力， 细胞（APC）在鼠皮肤癌细胞系上呈递TAA，用于体内和体内研究。 体外免疫反应 这些研究将检查某些 角质形成细胞和淋巴细胞衍生的细胞因子调节 表皮APC执行该功能。 这是有意义的，因为 原位LC的细胞因子微环境可能部分调节其 功能 UVR改变TAA经附睾呈递的能力 将具体审查APC。 此外，具体能力 非LC表皮元件和UVR扰动的低密度I-A+朗格汉斯 将检测呈递TAA用于免疫下调的细胞。 在 为了研究UVR干扰APC功能的可能机制， 蛋白质抗原加工和呈递的明确系统将是 利用。 实验将检查特定的可能作用， UVR诱导的APC膜生物学变化 包括LC在内的某些APC的功能。 更完整地理解 免疫系统与发育中的 皮肤恶性肿瘤和细胞因子和紫外线照射的机制， 影响这些过程可能有目前无法预见的治疗 影响

It has been demonstrated in certain strains of mice that, when ultraviolet radiation (UVR) is employed to induce cutaneous malignancies, specific immunologic changes occur in the animal as a direct consequence of UVR exposure and that these alterations in immune function serve to protect the tumor from immunologic destruction and allow its growth. It has been hypothesized that this may occur due to UVR-induced perturbations in Langerhans cells (LC) that prevent presentation of tumor associated antigens (TAA) for activation of immunologic effector mechanisms while allowing presentation of TAA by certain non-LC epidermal elements and/or UVR-altered LC for induction of immunologic down-regulation. This hypothesis is supported by data showing that, after exposure of LC to UVR in vitro, priming of mice provides a tolerogenic signal (if administered intravenously) rather than an immunogenic signal. Also, non-LC, epidermal elements, including Thy 1(+) dendritic epidermal cells (EC) and high-density : I-A+ EC, can present haptens for down-regulation of immunity with or without exposure to doses of UVR that alter LC function. However, direct functional evidence of a role for LC in tumor immunity is lacking. The experiments proposed herein will address this question. The objective of these studies is to examine the ability of epidermal antigen presenting cells (APC) to present TAA on murine skin cancer lines for in vivo and in vitro immune responses. These studies will examine whether certain keratinocyte and lymphocyte-derived cytokines modulate the ability of epidermal APC to perform this function. This is of interest since the cytokine microenvironment of the LC in situ may regulate, in part, its function. The ability of UVR to modify presentation of TAA by epidirmal APC will be specifically examined. In addition, the ability of specific non-LC epidermal elements and UVR-perturbed low density I-A+ Langerhans cells to present TAA for immunologic down-regulation will be examined. In order to examine possible mechanisms of UVR perturbation of APC function, well-defined systems of protein antigen processing and presentation will be utilized. Experiments will examine the possible roles of specific UVR-induced changes in APC-membrane biology in UVR-induced alterations in the function of certain APC including LC. A more complete understanding of the mechanisms by which the immune system interacts with developing cutaneous malignancies and the mechanisms by which cytokines and UVR may affect these process might have currently unforseen therapeutic implications.