TUMOR ANTIGEN PRESENTATION BY MICROGLIA

描述：肿瘤神经免疫学研究中的一个关键问题 关系到中枢神经系统启动和执行 一种免疫反应。在100%致死的大鼠恶性胶质瘤模型中， 分泌干扰素的转基因肿瘤在大脑内产生 免疫反应导致生存时间大幅延长，肿瘤 排斥反应和特定的系统免疫。白介素2由 转基因肿瘤不会改变人的生物学行为 转基因胶质瘤。Inf-‘诱导大鼠脑内主要蛋白表达增加 小胶质细胞中的组织相容性复合体I类和II类分子 并通过CD_4、CD_8、 和NK细胞。这些发现证明了免疫的成功。 通过在大脑中直接注射一种药物对抗中枢神经系统肿瘤 具有活生长能力的肿瘤疫苗。的广泛和长期目标 这项研究是为了澄清负责的基本原则 在大脑启动后启动免疫反应，并设计 新的免疫治疗策略用于治疗慢性粒细胞白血病患者 恶性脑瘤。本申请中提出的具体研究 旨在检查小胶质细胞发挥功能的能力 抗原提呈细胞对肿瘤特异性抗原的作用 组织相容性抗原I/II类分子与CD_4/CD_8细胞 启动这种免疫反应的启动。重要性和与健康的相关性 我们在动物身上的治疗结果就是这项研究的例证 这表明，在一个普遍致命的脑瘤模型中，95%的 脑内植入干扰素分泌肿瘤的大鼠存活 显著长于对照组，43%的人拒绝肿瘤和 发展保护性系统免疫。拟议研究的结果 将提供确凿的证据，证明小胶质细胞是否对 呈现中枢神经系统衍生的肿瘤抗原，这对设计未来至关重要 免疫治疗策略在治疗这两种疾病中的应用 原发或转移性脑瘤。

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.