EPIDERMAL ANTIGEN-PRESENTING CELLS AND TUMOR IMMUNITY

在某些品系的小鼠身上已经证明，当紫外线 辐射(UVR)被用来诱发皮肤恶性肿瘤，特异性 作为紫外线照射的直接后果，动物体内会发生免疫变化 这些免疫功能的改变有助于保护 使肿瘤免受免疫破坏，并使其生长。一直以来 假设这可能是由于UVR诱导的微扰 朗格汉斯细胞(LC)，防止肿瘤相关的表现 抗原(TAA)用于激活免疫效应机制，而 允许某些非LC表皮成分和/或 紫外线诱导免疫功能下调的LC。这 数据表明，在LC暴露于UVR后，这一假说得到了支持 在体外，小鼠的刺激提供了耐受的信号(如果给药的话 静脉注射)而不是免疫原性信号。此外，非LC，表皮 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 有或没有暴露于剂量的UVR会改变LC功能。然而， LC在肿瘤免疫中的作用缺乏直接的功能证据。 这里提出的实验将解决这个问题。目标是 这些研究中的一项是检查表皮抗原呈递的能力 细胞(APC)在小鼠皮肤癌细胞系体内和体内呈现TAA 体外免疫反应。这些研究将检验某些特定的 角质形成细胞和淋巴细胞衍生的细胞因子调节 表皮APC执行这一功能。这一点很有趣，因为 原位LC的细胞因子微环境可能部分调节其 功能。UVR通过附属器改变TAA表现的能力 将对APC进行专门审查。此外，特定的能力 非LC表皮细胞与UVR扰动低密度I-A+朗格汉斯 将检查呈现TAA以进行免疫下调的细胞。在……里面 为了研究APC函数的UVR扰动的可能机制， 明确定义的蛋白质抗原处理和呈递系统将是 被利用了。实验将考察特定分子可能扮演的角色 UVR对APC膜生物学的影响 包括LC在内的某些APC的功能。更全面地了解 免疫系统与发育相互作用的机制 皮肤恶性肿瘤及其细胞因子和UVR的作用机制 对这些过程的影响可能是目前未知的治疗方法 这意味着什么。

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.