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TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that an...

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Autores principales: Bottermann, Maria, Foss, Stian, van Tienen, Laurens M., Vaysburd, Marina, Cruickshank, James, O’Connell, Kevin, Clark, Jessica, Mayes, Keith, Higginson, Katie, Hirst, Jack C., McAdam, Martin B., Slodkowicz, Greg, Hutchinson, Edward, Kozik, Patrycja, Andersen, Jan Terje, James, Leo C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187179/
https://www.ncbi.nlm.nih.gov/pubmed/30209217
http://dx.doi.org/10.1073/pnas.1806314115
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author Bottermann, Maria
Foss, Stian
van Tienen, Laurens M.
Vaysburd, Marina
Cruickshank, James
O’Connell, Kevin
Clark, Jessica
Mayes, Keith
Higginson, Katie
Hirst, Jack C.
McAdam, Martin B.
Slodkowicz, Greg
Hutchinson, Edward
Kozik, Patrycja
Andersen, Jan Terje
James, Leo C.
author_facet Bottermann, Maria
Foss, Stian
van Tienen, Laurens M.
Vaysburd, Marina
Cruickshank, James
O’Connell, Kevin
Clark, Jessica
Mayes, Keith
Higginson, Katie
Hirst, Jack C.
McAdam, Martin B.
Slodkowicz, Greg
Hutchinson, Edward
Kozik, Patrycja
Andersen, Jan Terje
James, Leo C.
author_sort Bottermann, Maria
collection PubMed
description Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.
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spelling pubmed-61871792018-10-15 TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination Bottermann, Maria Foss, Stian van Tienen, Laurens M. Vaysburd, Marina Cruickshank, James O’Connell, Kevin Clark, Jessica Mayes, Keith Higginson, Katie Hirst, Jack C. McAdam, Martin B. Slodkowicz, Greg Hutchinson, Edward Kozik, Patrycja Andersen, Jan Terje James, Leo C. Proc Natl Acad Sci U S A Biological Sciences Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription. National Academy of Sciences 2018-10-09 2018-09-12 /pmc/articles/PMC6187179/ /pubmed/30209217 http://dx.doi.org/10.1073/pnas.1806314115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Bottermann, Maria
Foss, Stian
van Tienen, Laurens M.
Vaysburd, Marina
Cruickshank, James
O’Connell, Kevin
Clark, Jessica
Mayes, Keith
Higginson, Katie
Hirst, Jack C.
McAdam, Martin B.
Slodkowicz, Greg
Hutchinson, Edward
Kozik, Patrycja
Andersen, Jan Terje
James, Leo C.
TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title_full TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title_fullStr TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title_full_unstemmed TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title_short TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
title_sort trim21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187179/
https://www.ncbi.nlm.nih.gov/pubmed/30209217
http://dx.doi.org/10.1073/pnas.1806314115
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