PHYLOGENY OF HEAT SHOCK PROTEINS AND TUMOR IMMUNITY

描述（改编自研究者摘要）：热休克蛋白 （hsps）是在几乎所有细胞类型中发现的高度保守分子， 从原核生物到真核生物，它们在其中执行基本功能， 正常的和紧张的生理条件。 在哺乳动物中， 涉及免疫的多个方面，包括炎症， 自身免疫、抗原呈递和肿瘤免疫。 这些的作用 免疫功能中的蛋白质也是临床感兴趣的（例如，疫苗 发展）由于最近发现一些HSP（例如，gp96） 从小鼠癌细胞中纯化的抗体可以引发特异性保护性免疫， 在小鼠和大鼠中。 这项拟议中的研究将检验hsps 是免疫监视的祖先 为此，一种新的 肿瘤免疫将在两栖动物非洲爪蟾中进行研究， 稳定和良好表征的淋巴细胞系，其中每一种都已被 来自另一种自发性的非洲爪蟾胸腺瘤 两 MHC抗原表达不同的细胞系15/0和15/40， 来自克隆的LG-15青蛙的肿瘤。 模型是唯一一个 其中针对同系淋巴肿瘤的免疫应答可以 研究了一种变温脊椎动物。 此外，由于非洲爪蟾蝌蚪 不表达MHC I类抗原，直到变态， 可以确定I类肽在将hsps呈递给免疫系统中的作用。 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， 发现非洲爪蟾热休克蛋白可以引发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 解决了关于HSP免疫原性的基本问题， 基因限制。 实验计划：（1）定义，在同基因成人， 抗肿瘤免疫原性和特异性 用完整的辐射过的肿瘤细胞免疫，这些肿瘤细胞表达或不表达 MHC I类抗原;（2）在同基因成人中定义免疫原性， 佐剂性和特异性的抗肿瘤免疫引起的 用来自MHC I类阴性15/0淋巴细胞的gp 96免疫 肿瘤细胞系;（3）确定受刺激的效应系统 通过肿瘤细胞免疫原化和通过gp 96;和（4）定义 1类阴性肿瘤细胞和肿瘤衍生的gp 96的免疫原性 免疫活性的天然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.