TUMOR ANTIGEN PRESENTATION BY MICROGLIA

描述：肿瘤神经免疫学研究中的一个关键问题 涉及中枢神经系统启动和执行的能力 免疫反应 在100%致命的大鼠恶性神经胶质瘤模型中， 基因修饰的肿瘤分泌干扰素-'脑内产生一个 免疫应答导致生存时间、肿瘤 排斥反应和特异性系统免疫。 分泌的IL-2 转基因肿瘤不会改变肿瘤的生物学行为。 转染的神经胶质瘤 IFN-γ诱导主要的 小胶质细胞中组织相容性复合物I类和II类分子 并通过CD 4，CD 8， 和NK细胞。 这些发现证明了成功的免疫 针对中枢神经系统肿瘤，通过在脑中直接引发， 活的生长活性肿瘤疫苗 的广泛和长期目标 这项研究旨在阐明负责的基本原则 在大脑中引发免疫应答后启动，并设计 新的免疫策略，用于治疗患者 恶性脑瘤 本申请中提出的具体研究 目的是检查小胶质细胞的能力， 抗原提呈细胞对肿瘤特异性抗原的作用，以及主要 组织相容性抗原I/II类分子和CD 4/CD 8细胞的表达。 启动这种免疫反应。 重要性和健康相关性 我们在动物身上的治疗结果就是例证 这表明，在一个普遍致命的脑肿瘤模型中， 脑内植入分泌INF的肿瘤的大鼠存活 比对照组长得多，43%的人排斥肿瘤， 发展保护性系统免疫力。 拟议研究的结果 将提供决定性的证据，小胶质细胞是否负责 提出CNS衍生的肿瘤抗原，并为设计未来的关键 免疫策略，用于治疗患有以下疾病的患者： 原发性或转移性脑肿瘤。

DESCRIPTION: A crucial question in the study of tumor neuro-immunology concerns the capacity of the central nervous system to initiate and execute an immune response. In a 100 percent fatal rat malignant glioma model, genetically-modified tumors secreting INF-'intracerebrally generate an immune response resulting in a substantial increase in survival time, tumor rejection, and specific systemic immunity. IL-2 secreted by genetically-modified tumors does not change the biologic behavior of transfected gliomas. INF-' induces elevated expression of major histocompatibility complex class I and class II molecules in microglia throughout the brain and invokes enhanced tumor infiltration by CD4, CD8, and NK cells. These findings demonstrate the successful immunization against a central nervous system tumor by direct priming in the brain with a live growth-competent tumor vaccine. The broad and long term objectives of this research are to clarify the basic principles responsible for the initiation of an immune response after priming in the brain, and to devise novel immunotherapeutic strategies for the treatment of patients with malignant brain tumors. The specific research proposed in this application is intended to examine the capacity of microglia to function as competent antigen presenting cells to tumor specific antigens, and the role of major histocompatibility antigen class I/II molecules and CD4/CD8 cells in the initiation of such an immune response. The importance and health relevance of this research are exemplified by our therapeutic results in animals showing that, in a universally fatal brain tumor model, 95 percent of the rats implanted intracerebrally with INF-'-secreting tumors survive substantially longer than controls, and 43 percent reject the tumor and develop protective systemic immunity. The results of the proposed research will provide conclusive evidence whether microglia are responsible for presenting CNS-derived tumor antigens, and are crucial for designing future immunotherapeutic strategies for the treatment of patients with either primary or metastatic brain tumors.