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Immune response and immunoprotection against experimental tumors. Model: murine melanoma


Numerous attempts have been made in the last decades to apply concepts and experimental data on the immune response induced by malignant tumors to elaborate immunotherapeutic protocols, using a variety of immunizing agents. Monoclonal antibodies, irradiated tumor cells, transfected or not with cytokine genes, activated lymphocytes and NK cells, tumor-infiltrating lymphocytes, viral vectors with anti-sense nucleotide sequences or encoding interleukins and enzymes, and recently, gangliosides and other purified antigens, have been tested, rendering heterogenous and inconsistent results. By using the invasive murine melanoma model the Project alms at the systematic study of the immune response as a function of the implantation sites of the tumor and its metastatic evolution, the expression of surface markers, nature and specificity of the effector cells and of the anti-membrane antibodies, and the role of cytokines. It is assumed that a better knowledge of the characteristics of the tumor cell and of the various components of the immune system and their joint mobilization, may result in progress towards immunotherapy. More specifically, the Project is divided in 4 lines of investigation which will focus more closely on: a) The protective role of tumoral HSPs singly and with tumor induced antibodies, the nature of the effector cells elicited and their requirement for IFN-Y and perforin to show an anti-tumor effect; b) The expression of MHC I and 11 and co-stimulatory molecules in melanoma cells in comparison with normal and recently transformed melanocytes, and also the differential presentation of peptides inducing an immune response in these cell lines; c) The role of IFN-Y and perfonin in the natural evolution of the tumor; the specificity of the CTLs induced by in vivo expressed tumor antigens, their efficacy in destroying the tumor, depending or not on several interleukins and the protective role of dendritic cells as professional APCS; d) The study of the immunoprotection induced by recombinant viral vectors expressing different cytokines in various models of tumor transplantation. Development of this Project which involves advanced and updated methodology requires the setting up of preliminary operating conditions that are presently available at the UNONEX and collaborating laboratories. These conditions range from facilities and services to materials as follows: a) Established lines of murine melanoma, melanocytes and transformed melanocytes; b) Recombinant adenovirus encoding interleukins (obtained from the Riken DNA Bank), or without insert, nonreplicative; c) Animals knock-out for R-IFN-Y and perforin (among others) with haplotype compatible with that of murine melanoma B I 6F I 0, presently being bred at the CEDEME-LNIFESP;d) Excellent facilities and conditions for,the work on cellular and humoral immunology; e)Facilities and equipment (MALDI-TOF) for the analysis, sequencing and synthesis of peptides; f) Installed conditions for the construction of retroviral vectors, for transfection and gene expression; g) Installed conditions for the work on molecular biology, synthesis of oligonucleotides, PCR and construction of gene libraries; h) Facilities for histology and histochemistry. The Project is based on the expectation that a thorough analysis of the various elements of the natural and induced immune response against murine malignant melanoma may result in a better monitoring of the tumoral evolution x immunoprotective mechanisms as well as the modulation of the latter using the strategic mobilization of various cellular and humoral components which have been shown to be effective at the different stages of tumor growth. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CORREA, MARIANGELA; MACHADO JUNIOR, JOEL; CARNEIRO, CÉLIA R. W.; PESQUERO, JOÃO BOSCO; BADER, MICHAEL; CHAMMAS, ROGER; TRAVASSOS, LUIZ RODOLPHO RAJA GABAGLIA. Transient inflammatory response induced by apoptotic cells is an important mediator of melanoma cell engraftment and growth. International Journal of Cancer, v. 114, n. 3, p. 356-363, Apr. 2005.

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