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Theses

Identification d'Epitopes T CD4+ d'Antigènes tumoraux

Abstract : The induction of an effective immunity against tumours requires to recruit auxiliary and specific CD4+ T lymphocytes. Thus, the peptides of tumours presented by HLA II molecules are potential candidates for the anti-cancer immunotherapy. This work aimes at identifying new CD4+ T epitopes derived from three different antigens : Trag-3 (Taxol Resistant Associated Gene) (collaboration work) a tumour-specific antigen ; Survivin, an overexpressing antigen ; and the whole MAGE-A family, a collection of tumour-specific antigen. Yet, the use of peptide epitopes in vaccination requires to consider the polymorphism of HLA molecules in order to cover the maximum of individuals. As a result, we applied two different strategies of peptide identification, i.e. : 1) to identify the peptides presented by multiple molecules of HLA II (these peptides are called promiscuous épitopes). This strategy was applied to Trag-3 and Survivin ; 2) to identify the peptides presented by the molecules the most represented in the population : the HLA-DP4 molecules. This strategy was applied to the MAGE-A family. To seek the promiscuous épitopes, overlapping peptides covering the entire sequence of Trag-3 and Survivin were all synthesized and tested for their binding capacity with 12 molecules HLA-II (DR and DP). Immunogenicity of the peptides capable of binding to several molecules of HLA II was evaluated by the induction of CD4+ T lymphocytes. Finally a peptide of Trag-3 (P34-48) and 4 peptides of Survivin were revealed. Furthermore, spontaneous responses with respect to peptide Trag-3 34-48 were detected in the patients of cancers. To seek the epitopes restricted to the HLA-DP4, we established firstly a program to predict the potential HLA-DP4 binders. 9 genes of the MAGE-A family were subjected to the prediction. 12 predicted peptides were finally synthesized and tested in the binding test of HLA-DP4. 7 peptides having the best activity with the HLA-DP4 molecules were selected to evaluate their immunigenicity in vitro. Finally, 2 peptides of MAGE-A1 and a peptide of MAGE-A12 were revealed that they contain the epitopes naturally processed and presented in the native-antigen presentation. In conclusion, all peptides identified in this work present an interest for the design of peptide vaccines. We also proposed a prediction method for HLA-DP4 which significantly facilitates the selection among a large number of peptides..
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https://tel.archives-ouvertes.fr/tel-00362824
Contributor : Celine Lentz <>
Submitted on : Thursday, February 19, 2009 - 2:26:58 PM
Last modification on : Monday, February 10, 2020 - 6:12:52 PM
Long-term archiving on: : Saturday, November 26, 2016 - 5:52:36 AM

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  • HAL Id : tel-00362824, version 1

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Xiao-Fi Wang. Identification d'Epitopes T CD4+ d'Antigènes tumoraux. Sciences du Vivant [q-bio]. Institut national agronomique paris-grignon - INA P-G, 2007. Français. ⟨tel-00362824⟩

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