PHYLOGENY OF HEAT SHOCK PROTEINS AND TUMOR IMMUNITY

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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.