| Heat shock proteins (HSP), highly conserved and widely distributed in all prokaryotes and eukaryotes, are generally considered as molecular chaperone that take part in the regulation of protein translation, import and folding. HSPs normally constitute up to 5% of the total intracellular proteins. However, under stresses-such as exposure to high temperatures, toxins, oxidative conditions and glucose deprivation-their levels can rise to 15% or more. HSPs can be classified into ten families, each consisting of between one and five closely related proteins. The HSP70 family represents the most highly conserved of the HSPs, with functional counterparts found in the most primitive of bacteria and the most sophisticated of higher organisms. HSP70 are located in the cytosol and ensure the coordinated regulation of protein translocation, import and folding and limit cellular damage following stress by their ability to prevent protein aggregation and to restore the function of denatured proteins.La early approaches, cancers and their normal counterparts were analyzed by conventional chromatographic methods to identify cancer-rejection moleculesfrom cancers of diverse histological origins. The fractions thus obtained were used to immunize animals that were then challenged with live cancer cells. Surprisingly, all the well-characterized molecules identified by this method turned out to be HSP of the HSP90 or the HSP70 family. The immunological functions of HSP began to emerge when it was observed mat homogeneous preparations of certain HSP (such as gp96, HSP70 and HSP90) that were isolated from cancer cells elicited immunity to cancers, whereas corresponding preparations from normal tissues did not. The immunogenicity of tumor-derived HSP resulted from the associated HSP molecules with peptides that were generated by the degradation of proteins expressed by the cells from which the HSP were purified. Cancer specific antigens are generated by random mutations that accumulate in cancer cells because of continuous cell division and the genomic instability of cancers. So, the HSP-chaperoned peptides constitute the broad range of peptides generated in cancer cells. This function forms the basis of the cross-priming ability of HSP-peptide complexes. The randomness of the mutational process leads to an individually specific antigenic fingerprint for each cancer, accounting for the individually specific immunogenicity of nearly all cancers. HSP themselves act as adjuvants of mammalian origin.HSP have attracted much attention from an immunological point of view because the HSP isolated from cancers or virus infected cells can be used as adjuvant-free antitumor or antivirus vaccines in animals and activate cytotoxic T lymphocytes (CTL) in their MHC calss I presentation pathway. Even as little as nanomolar quantities of antigenic peptides complexed in vitro with gp96 or HSP70 are sufficient to induce a strong cytotoxic CD8+ T cell response. The mechanisms by which immunization with HSP-peptide complexes elicit potentantitumor, antiviral and antiparasitic effects are now becoming clear. The interaction of HSP-peptide complexes with antigen presenting cells (APC) such as macrophages or dendritic cells (DC) leads, on the one hand, to presenting antigenic peptides to CDS* and CD4+ T lymphocytes and, on the other hand, to a cacade of non-antigen-specific events that activate APC and promote immune response, including secretion of inflammatory cytokines tumor-necrosis-a, interleukin-lp, IL-12 by macrophages; secretion of chemokines such as MCP-1, MlP-la, RANTES by T cells; maturation of dendritic cells as measured by enhanced expression of MHC class n, CD86 and CD40. Matured DC can stimulate T cells to proliferate more effectively and then initiate immune response. The decreased immunogenicity of tumor cells is one of the main reason to escape immune surveillance, resulting in tolerance to tumor growth. It has been proved that the antitumor immunity mediated by T cells plays an important role in initiation of the adapti... |
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