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Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses

BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome...

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Autores principales: Dowling, David J., Scott, Evan A., Scheid, Annette, Bergelson, Ilana, Joshi, Sweta, Pietrasanta, Carlo, Brightman, Spencer, Sanchez-Schmitz, Guzman, Van Haren, Simon D., Ninković, Jana, Kats, Dina, Guiducci, Cristiana, de Titta, Alexandre, Bonner, Daniel K., Hirosue, Sachiko, Swartz, Melody A., Hubbell, Jeffrey A., Levy, Ofer
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mosby 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667586/
https://www.ncbi.nlm.nih.gov/pubmed/28343701
http://dx.doi.org/10.1016/j.jaci.2016.12.985
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author Dowling, David J.
Scott, Evan A.
Scheid, Annette
Bergelson, Ilana
Joshi, Sweta
Pietrasanta, Carlo
Brightman, Spencer
Sanchez-Schmitz, Guzman
Van Haren, Simon D.
Ninković, Jana
Kats, Dina
Guiducci, Cristiana
de Titta, Alexandre
Bonner, Daniel K.
Hirosue, Sachiko
Swartz, Melody A.
Hubbell, Jeffrey A.
Levy, Ofer
author_facet Dowling, David J.
Scott, Evan A.
Scheid, Annette
Bergelson, Ilana
Joshi, Sweta
Pietrasanta, Carlo
Brightman, Spencer
Sanchez-Schmitz, Guzman
Van Haren, Simon D.
Ninković, Jana
Kats, Dina
Guiducci, Cristiana
de Titta, Alexandre
Bonner, Daniel K.
Hirosue, Sachiko
Swartz, Melody A.
Hubbell, Jeffrey A.
Levy, Ofer
author_sort Dowling, David J.
collection PubMed
description BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. OBJECTIVE: Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. METHODS: Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist–encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow–derived DCs enabled benchmarking of the TLR8 agonist–encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25–loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. RESULTS: Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited T(H)-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist–adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4(+) T-cell numbers. CONCLUSION: TLR8 agonist–encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines.
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spelling pubmed-56675862017-11-09 Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses Dowling, David J. Scott, Evan A. Scheid, Annette Bergelson, Ilana Joshi, Sweta Pietrasanta, Carlo Brightman, Spencer Sanchez-Schmitz, Guzman Van Haren, Simon D. Ninković, Jana Kats, Dina Guiducci, Cristiana de Titta, Alexandre Bonner, Daniel K. Hirosue, Sachiko Swartz, Melody A. Hubbell, Jeffrey A. Levy, Ofer J Allergy Clin Immunol Article BACKGROUND: Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. OBJECTIVE: Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. METHODS: Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist–encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow–derived DCs enabled benchmarking of the TLR8 agonist–encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25–loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. RESULTS: Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited T(H)-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist–adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4(+) T-cell numbers. CONCLUSION: TLR8 agonist–encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines. Mosby 2017-11 /pmc/articles/PMC5667586/ /pubmed/28343701 http://dx.doi.org/10.1016/j.jaci.2016.12.985 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dowling, David J.
Scott, Evan A.
Scheid, Annette
Bergelson, Ilana
Joshi, Sweta
Pietrasanta, Carlo
Brightman, Spencer
Sanchez-Schmitz, Guzman
Van Haren, Simon D.
Ninković, Jana
Kats, Dina
Guiducci, Cristiana
de Titta, Alexandre
Bonner, Daniel K.
Hirosue, Sachiko
Swartz, Melody A.
Hubbell, Jeffrey A.
Levy, Ofer
Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title_full Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title_fullStr Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title_full_unstemmed Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title_short Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses
title_sort toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live bcg vaccine and enhance neonatal innate and adaptive immune responses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667586/
https://www.ncbi.nlm.nih.gov/pubmed/28343701
http://dx.doi.org/10.1016/j.jaci.2016.12.985
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