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Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56
A major roadblock in the development of novel vaccines is the formulation and delivery of the antigen. Liposomes composed of a dimethyldioctadecylammonium (DDA) backbone and the adjuvant trehalose-6-6-dibehenate (TDB, termed “cationic adjuvant formulation (CAF01)”, promote immunogenicity and protect...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125073/ https://www.ncbi.nlm.nih.gov/pubmed/32020284 http://dx.doi.org/10.1007/s00430-020-00657-3 |
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author | Kennerknecht, Kathrin Noschka, Reiner Löffler, Florian Wehrstedt, Stephanie Pedersen, Gabriel Kristian Mayer, Daniel Grieshober, Mark Christensen, Dennis Stenger, Steffen |
author_facet | Kennerknecht, Kathrin Noschka, Reiner Löffler, Florian Wehrstedt, Stephanie Pedersen, Gabriel Kristian Mayer, Daniel Grieshober, Mark Christensen, Dennis Stenger, Steffen |
author_sort | Kennerknecht, Kathrin |
collection | PubMed |
description | A major roadblock in the development of novel vaccines is the formulation and delivery of the antigen. Liposomes composed of a dimethyldioctadecylammonium (DDA) backbone and the adjuvant trehalose-6-6-dibehenate (TDB, termed “cationic adjuvant formulation (CAF01)”, promote immunogenicity and protective efficacy of vaccines, most notably against infection with Mycobacterium tuberculosis. Specifically, the multicomponent antigen H56 delivered by CAF01 protects against tuberculosis in mice. Here we investigated whether the inclusion of immune-modulatory adjuvants into CAF01 modulates the immunogenicity of H56/CAF01 in vitro and in vivo. Based on our recent findings we selected the active sequence of the mycobacterial 19 kDa lipoprotein, Pam(3)Cys, which interacts with Toll like receptor 2 to induce an antimicrobial pathway. H56/CAF01-Pam(3)Cys liposomes were characterized for Pam(3)Cys incorporation, size, toxicity and activation of primary human macrophages. Macrophages efficiently take up H56/CAF01-Pam(3)Cys and trigger the release of significantly higher levels of TNF, IL-12 and IL-10 than H56/CAF01 alone. To evaluate the immunogenicity in vivo, we immunized mice with H56/CAF01-Pam(3)Cys and measured the release of IFN-γ and IL-17A by lymph node cells and spleen cells. While the antigen-specific production of IFN-γ was reduced by inclusion of Pam(3)Cys into H56/CAF01, the levels of IL-17A remained unchanged. In agreement with this finding, the concentration of the IFN-γ-associated IgG2a antibodies in the serum was lower than in H56/CAF01 immunized animals. These results provide proof of concept that Toll like-receptor agonist can be included into liposomes to modulate immune responses. The discordant results between the in vitro studies with human macrophages and in vivo studies in mice highlight the relevance and complexity of comparing immune responses in different species |
format | Online Article Text |
id | pubmed-7125073 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-71250732020-04-06 Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 Kennerknecht, Kathrin Noschka, Reiner Löffler, Florian Wehrstedt, Stephanie Pedersen, Gabriel Kristian Mayer, Daniel Grieshober, Mark Christensen, Dennis Stenger, Steffen Med Microbiol Immunol Original Investigation A major roadblock in the development of novel vaccines is the formulation and delivery of the antigen. Liposomes composed of a dimethyldioctadecylammonium (DDA) backbone and the adjuvant trehalose-6-6-dibehenate (TDB, termed “cationic adjuvant formulation (CAF01)”, promote immunogenicity and protective efficacy of vaccines, most notably against infection with Mycobacterium tuberculosis. Specifically, the multicomponent antigen H56 delivered by CAF01 protects against tuberculosis in mice. Here we investigated whether the inclusion of immune-modulatory adjuvants into CAF01 modulates the immunogenicity of H56/CAF01 in vitro and in vivo. Based on our recent findings we selected the active sequence of the mycobacterial 19 kDa lipoprotein, Pam(3)Cys, which interacts with Toll like receptor 2 to induce an antimicrobial pathway. H56/CAF01-Pam(3)Cys liposomes were characterized for Pam(3)Cys incorporation, size, toxicity and activation of primary human macrophages. Macrophages efficiently take up H56/CAF01-Pam(3)Cys and trigger the release of significantly higher levels of TNF, IL-12 and IL-10 than H56/CAF01 alone. To evaluate the immunogenicity in vivo, we immunized mice with H56/CAF01-Pam(3)Cys and measured the release of IFN-γ and IL-17A by lymph node cells and spleen cells. While the antigen-specific production of IFN-γ was reduced by inclusion of Pam(3)Cys into H56/CAF01, the levels of IL-17A remained unchanged. In agreement with this finding, the concentration of the IFN-γ-associated IgG2a antibodies in the serum was lower than in H56/CAF01 immunized animals. These results provide proof of concept that Toll like-receptor agonist can be included into liposomes to modulate immune responses. The discordant results between the in vitro studies with human macrophages and in vivo studies in mice highlight the relevance and complexity of comparing immune responses in different species Springer Berlin Heidelberg 2020-02-04 2020 /pmc/articles/PMC7125073/ /pubmed/32020284 http://dx.doi.org/10.1007/s00430-020-00657-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Investigation Kennerknecht, Kathrin Noschka, Reiner Löffler, Florian Wehrstedt, Stephanie Pedersen, Gabriel Kristian Mayer, Daniel Grieshober, Mark Christensen, Dennis Stenger, Steffen Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title | Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title_full | Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title_fullStr | Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title_full_unstemmed | Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title_short | Toll like-receptor agonist Pam(3)Cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate H56 |
title_sort | toll like-receptor agonist pam(3)cys modulates the immunogenicity of liposomes containing the tuberculosis vaccine candidate h56 |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125073/ https://www.ncbi.nlm.nih.gov/pubmed/32020284 http://dx.doi.org/10.1007/s00430-020-00657-3 |
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