PHYLOGENY OF HEAT SHOCK PROTEINS AND TUMOR IMMUNITY

描述(摘自《研究人员摘要》)：热休克蛋白 热休克蛋白(HSPs)是高度保守的分子，几乎存在于所有类型的细胞中 原核生物到真核生物，在这些生物中，它们在 正常的和有压力的生理条件。在哺乳动物中，热休克蛋白是 参与免疫的多个方面，包括炎症， 自身免疫、抗原提呈和肿瘤免疫。这些因素的作用 免疫功能中的蛋白质也是临床上感兴趣的(例如，在疫苗中 发展)，因为最近发现一些热休克蛋白(如gp96) 从小鼠癌细胞中提纯可诱导特异性保护性免疫 在小鼠和大鼠身上。拟议的研究将检验热休克蛋白的假设 是免疫监视的祖传代理人。为此，一种新的模式 将在两栖类非洲爪哇中研究肿瘤免疫力，这种两栖动物利用 稳定且特性良好的淋巴细胞系，每一株都已 来自另一种自发发生的非洲爪哇胸腺肿瘤。二 表达MHC抗原不同的细胞系15/0和15/40具有 是从克隆的LG-15青蛙的肿瘤中提取的。这款车是唯一的 其中针对同基因淋巴样肿瘤的免疫反应可以 在一种外温脊椎动物中研究的。此外，由于非洲爪哇的蝌蚪 在变态之前不表达MHC I类抗原，重要的是 可以确定将热休克蛋白呈递给免疫系统的I类多肽。 考虑到青蛙的免疫系统和 哺乳动物，尽管它们的起源相隔数百万年，但 非洲爪哇热休克蛋白能诱导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 这些分子的临床潜力。此外，拟议的实验 解决有关热休克蛋白免疫原性的基本问题 在系统发育上受到限制。 计划进行的实验是：(1)在同基因的成人中定义 沙门氏菌诱导抗肿瘤免疫的免疫原性和特异性 用有表达和不表达的完整照射的肿瘤细胞进行免疫 MHC I类抗原；(2)在同基因成人中定义免疫原性， 抗肿瘤免疫的佐剂性和特异性 MHC I类阴性15/0淋巴组织来源的gp96免疫 肿瘤细胞系；(3)定义正在被刺激的效应系统(S) 通过肿瘤细胞免疫原性和gp96；和(4)定义 1类阴性肿瘤细胞和肿瘤来源gp96的免疫原性 免疫能力天然的1类缺陷蝌蚪。

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.