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Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy

High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced i...

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Autores principales: Emami, Michael R., Espinoza, Alejandro, Young, Courtney S., Ma, Feiyang, Farahat, Philip K., Felgner, Philip L., Chamberlain, Jeffrey S., Xu, Xiangmin, Pyle, April D., Pellegrini, Matteo, Villalta, S. Armando, Spencer, Melissa J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512012/
https://www.ncbi.nlm.nih.gov/pubmed/37746243
http://dx.doi.org/10.1016/j.omtm.2023.06.002
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author Emami, Michael R.
Espinoza, Alejandro
Young, Courtney S.
Ma, Feiyang
Farahat, Philip K.
Felgner, Philip L.
Chamberlain, Jeffrey S.
Xu, Xiangmin
Pyle, April D.
Pellegrini, Matteo
Villalta, S. Armando
Spencer, Melissa J.
author_facet Emami, Michael R.
Espinoza, Alejandro
Young, Courtney S.
Ma, Feiyang
Farahat, Philip K.
Felgner, Philip L.
Chamberlain, Jeffrey S.
Xu, Xiangmin
Pyle, April D.
Pellegrini, Matteo
Villalta, S. Armando
Spencer, Melissa J.
author_sort Emami, Michael R.
collection PubMed
description High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced immune responses. Here, we show that mice dual-dosed with AAV9 at 4-week intervals better recapitulate aspects of human immunity to AAV. In the model, anti-AAV9 immunoglobulin G (IgGs) increased in a linear fashion between the first and second AAV administrations. Complement activation was only observed in the presence of high levels of both AAV and anti-AAV IgG. Myeloid-derived pro-inflammatory cytokines were significantly induced in the same pattern as complement activation, suggesting that myeloid cell activation to AAV may rely on the presence of both AAV and anti-AAV IgG complexes. Single-cell RNA sequencing of peripheral blood mononuclear cells confirmed that activated monocytes were a primary source of pro-inflammatory cytokines and chemokines, which were significantly increased after a second AAV9 exposure. The same activated monocyte clusters expressed both Fcγ and complement receptors, suggesting that anti-AAV-mediated activation of myeloid cells through Fcγ receptors and/or complement receptors is one mechanism by which anti-AAV antigen complexes may prime antigen-presenting cells and amplify downstream immunity.
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spelling pubmed-105120122023-09-22 Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy Emami, Michael R. Espinoza, Alejandro Young, Courtney S. Ma, Feiyang Farahat, Philip K. Felgner, Philip L. Chamberlain, Jeffrey S. Xu, Xiangmin Pyle, April D. Pellegrini, Matteo Villalta, S. Armando Spencer, Melissa J. Mol Ther Methods Clin Dev Original Article High systemic doses of adeno-associated viruses (AAVs) have been associated with immune-related serious adverse events (SAEs). Although AAV was well tolerated in preclinical models, SAEs were observed in clinical trials, indicating the need for improved preclinical models to understand AAV-induced immune responses. Here, we show that mice dual-dosed with AAV9 at 4-week intervals better recapitulate aspects of human immunity to AAV. In the model, anti-AAV9 immunoglobulin G (IgGs) increased in a linear fashion between the first and second AAV administrations. Complement activation was only observed in the presence of high levels of both AAV and anti-AAV IgG. Myeloid-derived pro-inflammatory cytokines were significantly induced in the same pattern as complement activation, suggesting that myeloid cell activation to AAV may rely on the presence of both AAV and anti-AAV IgG complexes. Single-cell RNA sequencing of peripheral blood mononuclear cells confirmed that activated monocytes were a primary source of pro-inflammatory cytokines and chemokines, which were significantly increased after a second AAV9 exposure. The same activated monocyte clusters expressed both Fcγ and complement receptors, suggesting that anti-AAV-mediated activation of myeloid cells through Fcγ receptors and/or complement receptors is one mechanism by which anti-AAV antigen complexes may prime antigen-presenting cells and amplify downstream immunity. American Society of Gene & Cell Therapy 2023-06-12 /pmc/articles/PMC10512012/ /pubmed/37746243 http://dx.doi.org/10.1016/j.omtm.2023.06.002 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Emami, Michael R.
Espinoza, Alejandro
Young, Courtney S.
Ma, Feiyang
Farahat, Philip K.
Felgner, Philip L.
Chamberlain, Jeffrey S.
Xu, Xiangmin
Pyle, April D.
Pellegrini, Matteo
Villalta, S. Armando
Spencer, Melissa J.
Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title_full Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title_fullStr Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title_full_unstemmed Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title_short Innate and adaptive AAV-mediated immune responses in a mouse model of Duchenne muscular dystrophy
title_sort innate and adaptive aav-mediated immune responses in a mouse model of duchenne muscular dystrophy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512012/
https://www.ncbi.nlm.nih.gov/pubmed/37746243
http://dx.doi.org/10.1016/j.omtm.2023.06.002
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