Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.

<h4>Background</h4>There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted p...

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Autores principales:	Negar Seyed, Tahereh Taheri, Charline Vauchy, Magalie Dosset, Yann Godet, Ali Eslamifar, Iraj Sharifi, Olivier Adotevi, Christophe Borg, Pierre Simon Rohrlich, Sima Rafati
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/586a79a565c347619afe11eea5e6c25f
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spelling	oai:doaj.org-article:586a79a565c347619afe11eea5e6c25f2021-11-25T05:56:57ZImmunogenicity evaluation of a rationally designed polytope construct encoding HLA-A0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.1932-620310.1371/journal.pone.0108848https://doaj.org/article/586a79a565c347619afe11eea5e6c25f2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0108848https://doaj.org/toc/1932-6203<h4>Background</h4>There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the MHC-class-I and II.<h4>Methods and findings</h4>HLA-A0201 restricted epitopes from LPG-3, LmSTI-1, CPB and CPC along with H-2Kd restricted peptides, were lined-up together as a polytope string in a DNA construct. Polytope string was rationally designed by harnessing advantages of ubiquitin, spacers and HLA-DR restricted Th1 epitope. Endotoxin free pcDNA plasmid expressing the polytope was inoculated into humanized HLA-DRB10101/HLA-A0201 transgenic mice intramuscularly 4 days after Cardiotoxin priming followed by 2 boosters at one week interval. Mice were sacrificed 10 days after the last booster, and splenocytes were subjected to ex-vivo and in-vitro evaluation of specific IFN-γ production and in-vitro cytotoxicity against individual peptides by ELISpot and standard chromium-51 (51Cr) release assay respectively. 4 H-2Kd and 5 HLA-A*0201 restricted peptides were able to induce specific CD8 T cell responses in BALB/C and HLA-A2/DR1 mice respectively. IFN-γ and cytolytic activity together discriminated LPG-3-P1 as dominant, LmSTI-1-P3 and LmSTI-1-P6 as subdominant with both cytolytic activity and IFN-γ production, LmSTI-1-P4 and LPG-3-P5 as subdominant with only IFN-γ production potential.<h4>Conclusions</h4>Here we described a new DNA-polytope construct for Leishmania vaccination encompassing immunogenic HLA-A2 restricted peptides. Immunogenicity evaluation in HLA-transgenic model confirmed CD8 T cell induction with expected affinities and avidities showing almost efficient processing and presentation of the peptides in relevant preclinical model. Further evaluation will determine the efficacy of this polytope construct protecting against infectious challenge of Leishmania. Fortunately HLA transgenic mice are promising preclinical models helping to speed up immunogenicity analysis in a human related mouse model.Negar SeyedTahereh TaheriCharline VauchyMagalie DossetYann GodetAli EslamifarIraj SharifiOlivier AdoteviChristophe BorgPierre Simon RohrlichSima RafatiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e108848 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Negar Seyed Tahereh Taheri Charline Vauchy Magalie Dosset Yann Godet Ali Eslamifar Iraj Sharifi Olivier Adotevi Christophe Borg Pierre Simon Rohrlich Sima Rafati Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
description	<h4>Background</h4>There are several reports demonstrating the role of CD8 T cells against Leishmania species. Therefore peptide vaccine might represent an effective approach to control the infection. We developed a rational polytope-DNA construct encoding immunogenic HLA-A2 restricted peptides and validated the processing and presentation of encoded epitopes in a preclinical mouse model humanized for the MHC-class-I and II.<h4>Methods and findings</h4>HLA-A0201 restricted epitopes from LPG-3, LmSTI-1, CPB and CPC along with H-2Kd restricted peptides, were lined-up together as a polytope string in a DNA construct. Polytope string was rationally designed by harnessing advantages of ubiquitin, spacers and HLA-DR restricted Th1 epitope. Endotoxin free pcDNA plasmid expressing the polytope was inoculated into humanized HLA-DRB10101/HLA-A0201 transgenic mice intramuscularly 4 days after Cardiotoxin priming followed by 2 boosters at one week interval. Mice were sacrificed 10 days after the last booster, and splenocytes were subjected to ex-vivo and in-vitro evaluation of specific IFN-γ production and in-vitro cytotoxicity against individual peptides by ELISpot and standard chromium-51 (51Cr) release assay respectively. 4 H-2Kd and 5 HLA-A0201 restricted peptides were able to induce specific CD8 T cell responses in BALB/C and HLA-A2/DR1 mice respectively. IFN-γ and cytolytic activity together discriminated LPG-3-P1 as dominant, LmSTI-1-P3 and LmSTI-1-P6 as subdominant with both cytolytic activity and IFN-γ production, LmSTI-1-P4 and LPG-3-P5 as subdominant with only IFN-γ production potential.<h4>Conclusions</h4>Here we described a new DNA-polytope construct for Leishmania vaccination encompassing immunogenic HLA-A2 restricted peptides. Immunogenicity evaluation in HLA-transgenic model confirmed CD8 T cell induction with expected affinities and avidities showing almost efficient processing and presentation of the peptides in relevant preclinical model. Further evaluation will determine the efficacy of this polytope construct protecting against infectious challenge of Leishmania. Fortunately HLA transgenic mice are promising preclinical models helping to speed up immunogenicity analysis in a human related mouse model.
format	article
author	Negar Seyed Tahereh Taheri Charline Vauchy Magalie Dosset Yann Godet Ali Eslamifar Iraj Sharifi Olivier Adotevi Christophe Borg Pierre Simon Rohrlich Sima Rafati
author_facet	Negar Seyed Tahereh Taheri Charline Vauchy Magalie Dosset Yann Godet Ali Eslamifar Iraj Sharifi Olivier Adotevi Christophe Borg Pierre Simon Rohrlich Sima Rafati
author_sort	Negar Seyed
title	Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
title_short	Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
title_full	Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
title_fullStr	Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
title_full_unstemmed	Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.
title_sort	immunogenicity evaluation of a rationally designed polytope construct encoding hla-a*0201 restricted epitopes derived from leishmania major related proteins in hla-a2/dr1 transgenic mice: steps toward polytope vaccine.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/586a79a565c347619afe11eea5e6c25f
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Immunogenicity evaluation of a rationally designed polytope construct encoding HLA-A*0201 restricted epitopes derived from Leishmania major related proteins in HLA-A2/DR1 transgenic mice: steps toward polytope vaccine.

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