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AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes
Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588448/ https://www.ncbi.nlm.nih.gov/pubmed/26445723 http://dx.doi.org/10.1038/mtm.2015.29 |
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author | Hui, Daniel J Edmonson, Shyrie C Podsakoff, Gregory M Pien, Gary C Ivanciu, Lacramioara Camire, Rodney M Ertl, Hildegund Mingozzi, Federico High, Katherine A Basner-Tschakarjan, Etiena |
author_facet | Hui, Daniel J Edmonson, Shyrie C Podsakoff, Gregory M Pien, Gary C Ivanciu, Lacramioara Camire, Rodney M Ertl, Hildegund Mingozzi, Federico High, Katherine A Basner-Tschakarjan, Etiena |
author_sort | Hui, Daniel J |
collection | PubMed |
description | Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings. |
format | Online Article Text |
id | pubmed-4588448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45884482015-10-06 AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes Hui, Daniel J Edmonson, Shyrie C Podsakoff, Gregory M Pien, Gary C Ivanciu, Lacramioara Camire, Rodney M Ertl, Hildegund Mingozzi, Federico High, Katherine A Basner-Tschakarjan, Etiena Mol Ther Methods Clin Dev Article Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings. Nature Publishing Group 2015-09-30 /pmc/articles/PMC4588448/ /pubmed/26445723 http://dx.doi.org/10.1038/mtm.2015.29 Text en Copyright © 2015 Official journal of the American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Article Hui, Daniel J Edmonson, Shyrie C Podsakoff, Gregory M Pien, Gary C Ivanciu, Lacramioara Camire, Rodney M Ertl, Hildegund Mingozzi, Federico High, Katherine A Basner-Tschakarjan, Etiena AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title | AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title_full | AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title_fullStr | AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title_full_unstemmed | AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title_short | AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes |
title_sort | aav capsid cd8+ t-cell epitopes are highly conserved across aav serotypes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588448/ https://www.ncbi.nlm.nih.gov/pubmed/26445723 http://dx.doi.org/10.1038/mtm.2015.29 |
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