The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration
•CpG dinucleotides in the AAV vector genome negatively impacts gene transfer and expression.•With an antibody-encoding transgene, this effect is observed at 24 h after AAV administration.•Plasmacytoid DC-like myeloid cells expressing Fc receptor are activated after AAV administration. AAV-mediated g...
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Veröffentlicht in: | Cellular immunology 2024-05, Vol.399-400, p.104823-104823, Article 104823 |
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container_title | Cellular immunology |
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creator | Glenn, Justin D. Negash, Henos Henry, William Qian, Randolph Liu, Ye Danos, Olivier Bruder, Joseph T. Karumuthil-Melethil, Subha |
description | •CpG dinucleotides in the AAV vector genome negatively impacts gene transfer and expression.•With an antibody-encoding transgene, this effect is observed at 24 h after AAV administration.•Plasmacytoid DC-like myeloid cells expressing Fc receptor are activated after AAV administration.
AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2–3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population. |
doi_str_mv | 10.1016/j.cellimm.2024.104823 |
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AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2–3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.</description><identifier>ISSN: 0008-8749</identifier><identifier>EISSN: 1090-2163</identifier><identifier>DOI: 10.1016/j.cellimm.2024.104823</identifier><identifier>PMID: 38520831</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>AAV ; Animals ; CpG Islands - genetics ; CpG Islands - immunology ; Dendritic Cells - immunology ; Dependovirus - genetics ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors ; Innate immunity ; Mice ; Mice, Inbred C57BL ; Myeloid cell ; Plasmacytoid dendritic cell ; Receptors, IgG - genetics ; Receptors, IgG - immunology ; Receptors, IgG - metabolism ; TLR9 ; Toll-Like Receptor 9 - immunology ; Transgenes</subject><ispartof>Cellular immunology, 2024-05, Vol.399-400, p.104823-104823, Article 104823</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-974adee4f6649c6b25b774a72ed449c73cdce57a6a656d8f46a23cd87098ba8a3</citedby><cites>FETCH-LOGICAL-c365t-974adee4f6649c6b25b774a72ed449c73cdce57a6a656d8f46a23cd87098ba8a3</cites><orcidid>0000-0002-3567-6233</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cellimm.2024.104823$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38520831$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Glenn, Justin D.</creatorcontrib><creatorcontrib>Negash, Henos</creatorcontrib><creatorcontrib>Henry, William</creatorcontrib><creatorcontrib>Qian, Randolph</creatorcontrib><creatorcontrib>Liu, Ye</creatorcontrib><creatorcontrib>Danos, Olivier</creatorcontrib><creatorcontrib>Bruder, Joseph T.</creatorcontrib><creatorcontrib>Karumuthil-Melethil, Subha</creatorcontrib><title>The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration</title><title>Cellular immunology</title><addtitle>Cell Immunol</addtitle><description>•CpG dinucleotides in the AAV vector genome negatively impacts gene transfer and expression.•With an antibody-encoding transgene, this effect is observed at 24 h after AAV administration.•Plasmacytoid DC-like myeloid cells expressing Fc receptor are activated after AAV administration.
AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2–3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.</description><subject>AAV</subject><subject>Animals</subject><subject>CpG Islands - genetics</subject><subject>CpG Islands - immunology</subject><subject>Dendritic Cells - immunology</subject><subject>Dependovirus - genetics</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors</subject><subject>Innate immunity</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Myeloid cell</subject><subject>Plasmacytoid dendritic cell</subject><subject>Receptors, IgG - genetics</subject><subject>Receptors, IgG - immunology</subject><subject>Receptors, IgG - metabolism</subject><subject>TLR9</subject><subject>Toll-Like Receptor 9 - immunology</subject><subject>Transgenes</subject><issn>0008-8749</issn><issn>1090-2163</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1v3CAURFGjZPPxE1Jx7MVbwBjjU7VaNUmlSLkkuSIWnhO2tnEBR_If6O8uzm577Qlp3sybxwxCN5SsKaHi635toOtc368ZYTxjXLLyBK0oaUjBqCg_oRUhRBay5s05uohxTwilvCFn6LyUFSOypCv0--kN8BggwmAA-xZvx7uI3YA3mxf8CgPg9AZBjzN-B5N8WGZ2MhCxxmOnY6_NnLyz2MJgg0vO4OWuonM_814_Tp1Ozg9ZHWYMOnQz1m2CgLXt3eBiCh_zK3Ta6i7C9fG9RM-335-298XD492P7eahMKWoUtHUXFsA3grBGyN2rNrVGaoZWJ6BujTWQFVroUUlrGy50CxjsiaN3Gmpy0v05bB3DP7XBDGp3sXlYD2An6Ji2YEQUVUyU6sD1QQfY4BWjcH1OsyKErVUoPbqWIFaKlCHCrLu89Fi2vVg_6n-Zp4J3w4EyB99dxBUNG6J37qQM1bWu_9Y_AG7Zpy4</recordid><startdate>202405</startdate><enddate>202405</enddate><creator>Glenn, Justin D.</creator><creator>Negash, Henos</creator><creator>Henry, William</creator><creator>Qian, Randolph</creator><creator>Liu, Ye</creator><creator>Danos, Olivier</creator><creator>Bruder, Joseph T.</creator><creator>Karumuthil-Melethil, Subha</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3567-6233</orcidid></search><sort><creationdate>202405</creationdate><title>The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration</title><author>Glenn, Justin D. ; Negash, Henos ; Henry, William ; Qian, Randolph ; Liu, Ye ; Danos, Olivier ; Bruder, Joseph T. ; Karumuthil-Melethil, Subha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-974adee4f6649c6b25b774a72ed449c73cdce57a6a656d8f46a23cd87098ba8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>AAV</topic><topic>Animals</topic><topic>CpG Islands - genetics</topic><topic>CpG Islands - immunology</topic><topic>Dendritic Cells - immunology</topic><topic>Dependovirus - genetics</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors</topic><topic>Innate immunity</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Myeloid cell</topic><topic>Plasmacytoid dendritic cell</topic><topic>Receptors, IgG - genetics</topic><topic>Receptors, IgG - immunology</topic><topic>Receptors, IgG - metabolism</topic><topic>TLR9</topic><topic>Toll-Like Receptor 9 - immunology</topic><topic>Transgenes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Glenn, Justin D.</creatorcontrib><creatorcontrib>Negash, Henos</creatorcontrib><creatorcontrib>Henry, William</creatorcontrib><creatorcontrib>Qian, Randolph</creatorcontrib><creatorcontrib>Liu, Ye</creatorcontrib><creatorcontrib>Danos, Olivier</creatorcontrib><creatorcontrib>Bruder, Joseph T.</creatorcontrib><creatorcontrib>Karumuthil-Melethil, Subha</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cellular immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Glenn, Justin D.</au><au>Negash, Henos</au><au>Henry, William</au><au>Qian, Randolph</au><au>Liu, Ye</au><au>Danos, Olivier</au><au>Bruder, Joseph T.</au><au>Karumuthil-Melethil, Subha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration</atitle><jtitle>Cellular immunology</jtitle><addtitle>Cell Immunol</addtitle><date>2024-05</date><risdate>2024</risdate><volume>399-400</volume><spage>104823</spage><epage>104823</epage><pages>104823-104823</pages><artnum>104823</artnum><issn>0008-8749</issn><eissn>1090-2163</eissn><abstract>•CpG dinucleotides in the AAV vector genome negatively impacts gene transfer and expression.•With an antibody-encoding transgene, this effect is observed at 24 h after AAV administration.•Plasmacytoid DC-like myeloid cells expressing Fc receptor are activated after AAV administration.
AAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2–3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>38520831</pmid><doi>10.1016/j.cellimm.2024.104823</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-3567-6233</orcidid></addata></record> |
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subjects | AAV Animals CpG Islands - genetics CpG Islands - immunology Dendritic Cells - immunology Dependovirus - genetics Gene therapy Genetic Therapy - methods Genetic Vectors Innate immunity Mice Mice, Inbred C57BL Myeloid cell Plasmacytoid dendritic cell Receptors, IgG - genetics Receptors, IgG - immunology Receptors, IgG - metabolism TLR9 Toll-Like Receptor 9 - immunology Transgenes |
title | The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration |
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