IMMUNOLOGICAL ROLE OF THE STRESS INDUCIBLE HSP70

应激诱导 HSP70 的免疫作用

• 批准号: 6342199
• 负责人: ANTOINE L. MENORET
• 金额: $ 19.88万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342199
• 关键词: binding proteins; cytotoxic T lymphocyte; heat shock proteins; laboratory mouse; leukocyte activation /transformation; molecular chaperones; neoplasm /cancer immunology; peptides; protein biosynthesis; protein purification; tissue /cell culture; transfection

My laboratory has previously found that the immunogenicity of tumor cells cosegregates with the expression of the inducible hsp70 but not with the constitutive hsc70. Various clones derived from the same primary tumor were either spontaneously rejected by the alphabeta-TCR positive cell component of the immune system or grew progressively and killed the host. Surprisingly, classical immunological markers like MHC-I, MHC-II, I-CAM and others where not associated with this difference of behavior in vivo. We observed that clones having the ability to synthesize the strictly inducible hsp70 were rejected by the immune system. Conversely, the clones that grew progressively do not synthesize the inducible hsp70 synthesis. This cosegregation was confirmed by the selection of multiple variants, independently of the expression of the constitutive hsc70 and of other immunological markers. We propose to : (i) Purify the inducible hsp70 and the constitutive hsc70 from tumor cells and determine their respective immunogenicity. (ii) Genetically manipulate the hsp70 and hsc70 specific domains in order to study their requirements for their unique immunological properties. (iii) Analyze the peptides associated with inducible hsp70 and constitutive hsc70. The study of the strictly inducible hsp70 participates in both the fundamental understanding of the immune system and the new generation of HSP-based anti-cancer vaccines. The HSP70-derived tumors have been used successfully against murine cancers and are currently under investigation in humans. The possibility that the inducible HSPs have a superior immunogenicity than the constitutively expressed HSPs has not been explored so far and might be of considerable benefit for public health.

我的实验室之前发现肿瘤细胞的免疫原性与诱导型 hsp70 的表达共分离，但与组成型 hsc70 不共分离。 来自同一原发性肿瘤的各种克隆要么被免疫系统的alpha-TCR阳性细胞成分自发排斥，要么逐渐生长并杀死宿主。令人惊讶的是，MHC-I、MHC-II、I-CAM 等经典免疫标记物与这种体内行为差异无关。 我们观察到具有合成严格诱导型 hsp70 能力的克隆被免疫系统排斥。相反，逐渐生长的克隆不合成诱导型 hsp70。 这种共分离通过多个变体的选择得到证实，与组成型 hsc70 和其他免疫标记物的表达无关。我们建议：（i）从肿瘤细胞中纯化诱导型 hsp70 和组成型 hsc70，并确定它们各自的免疫原性。 (ii) 对 hsp70 和 hsc70 特定结构域进行基因操作，以研究它们对其独特免疫学特性的要求。 (iii) 分析与诱导型 hsp70 和组成型 hsc70 相关的肽。严格诱导型hsp70的研究既涉及对免疫系统的基础认识，也涉及新一代基于HSP的抗癌疫苗。 HSP70 衍生的肿瘤已成功用于治疗小鼠癌症，目前正在人类身上进行研究。 迄今为止，诱导型热休克蛋白比组成型表达的热休克蛋白具有更好的免疫原性的可能性尚未被探索，并且可能对公共健康具有相当大的益处。