PHYLOGENY OF HEAT SHOCK PROTEINS AND TUMOR IMMUNITY

热休克蛋白和肿瘤免疫的系统发育

• 批准号: 2896259
• 负责人: Nicholas Cohen
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896259
• 关键词: Xenopus; biochemical evolution; immature animal; leukocyte activation /transformation; macrophage; mature animal; natural killer cells; neoplasm /cancer immunology; passive immunization; stress proteins; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's Abstract): Heat shock proteins (hsps) are highly conserved molecules found in almost all cell types from prokaryotes to eukaryotes where they perform essential functions under normal as well as stressful physiological conditions. In mammals, hsps are involved in multiple facets of immunity including inflammation, autoimmunity, antigen presentation, and tumor immunity. The role of these proteins in immune function is also of clinical interest (e.g., in vaccine development) owing to the recent discovery that some hsps (e.g., gp96) purified from murine cancer cells can elicit a specific protective immunity in mice and rats. The proposed research will test the hypothesis that hsps are ancestral agents of immune surveillance. To this end, a new model of tumor immunity will be studied in the amphibian Xenopus that makes use of stable and well characterized lymphoid cell lines, each of which has been derived from a different spontaneously occurring Xenopus thymic tumor. Two cell lines, 15/0 and 15/40, which differ in expression of MHC antigens, have been derived from tumors in cloned LG-15 frogs. The model is the only one in which immune responses directed against syngeneic lymphoid tumors can be studied in an ectothermic vertebrate. Moreover, since Xenopus tadpoles do not express MHC class I antigens until metamorphosis, the importance of class I peptides in presenting hsps to the immune system can be determined. Given the remarkable similarity between the immune system of frogs and mammals, despite the millions of years that separate their origins, the finding that Xenopus hsps can elicit potent anti-tumor immune responses would certainly support the fundamental immunobiological importance and clinical potential of these molecules. Moreover, the proposed experiments address fundamental questions about hsp immunogenicity that are not phylogenetically restricted. Experiments are planned to: (1) define, in isogeneic adults, the immunogenicity and specificity of anti-tumor immunity elicited by immunization with intact irradiated tumor cells that do, and do not, express MHC class I antigens; (2) define, in isogeneic adults, the immunogenicity, adjuvanticity, and specificity of anti-tumor immunity elicited by immunization with gp96 derived from the MHC class I-negative 15/0 lymphoid tumor cell line; (3) define the effector system(s) that are being stimulated by tumor cell immunogenization and by gp96; and (4) define the immunogenicity of class 1-negative tumor cells and tumor-derived gp96 in immunocompetent naturally class 1-deficient tadpoles.

描述（改编自调查员的摘要）：热激蛋白 （HSP）是在几乎所有细胞类型中发现的高度保守分子 原核生物到真核生物，在这些真核生物下执行基本功能 正常和压力的生理条件。 在哺乳动物中，HSP是 参与多个免疫力方面，包括炎症， 自身免疫性，抗原表现和肿瘤免疫力。 这些的作用 免疫功能中的蛋白质也具有临床意义（例如，在疫苗中 由于最近的发现，某些HSP（例如GP96），开发） 从鼠类癌细胞中纯化会引起特定的保护性免疫力 在老鼠和老鼠中。 拟议的研究将检验HSP的假设 是免疫监测的祖先药物。 为此，一个新的模型 将在使用的两栖动物中研究肿瘤免疫力 稳定且表征良好的淋巴样细胞系，每种细胞系已 源自不同自发发生的爪蟾胸腺肿瘤。 二 细胞系，15/0和15/40，在MHC抗原的表达上有所不同，具有 是源自克隆的LG-15青蛙中的肿瘤。 该模型是唯一的 其中针对合成性淋巴样肿瘤的免疫反应可以是 在热热脊椎动物中进行了研究。 此外，由于爪蟾to to 直到变形之前，才表达MHC I类抗原的重要性 可以确定将HSP呈现给免疫系统的I类肽。 考虑到青蛙的免疫系统与 哺乳动物，尽管有数百万年的起源，但 发现爪蟾HSP可以引起有效的抗肿瘤免疫反应 肯定会支持基本的免疫生物学重要性，并且 这些分子的临床潜力。 此外，提出的实验 解决有关HSP免疫原性的基本问题 系统发育限制。 计划实验：（1）定义，在异教徒成年人中定义 抗肿瘤免疫的免疫原性和特异性 用完整的辐照肿瘤细胞进行免疫，并且不表达 MHC I类抗原； （2）定义在异种成年人中，免疫原性， 辅助性和抗肿瘤免疫的特异性 源自MHC I类15/0淋巴的GP96免疫 肿瘤细胞系； （3）定义正在刺激的效应系统 通过肿瘤细胞免疫原和GP96； （4）定义 1类阴性肿瘤细胞和肿瘤衍生的GP96的免疫原性 免疫能力自然1级缺陷t。