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Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors

Transitioning to human trials from pre-clinical models resulted in the emergence of inhibitory AAV vector immune responses which has become a hurdle for sustained correction. Early animal studies did not predict the full range of host immunity to the AAV vector in human studies. While pre-existing a...

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Autores principales: Basner-Tschakarjan, Etiena, Bijjiga, Enoch, Martino, Ashley T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916775/
https://www.ncbi.nlm.nih.gov/pubmed/24570676
http://dx.doi.org/10.3389/fimmu.2014.00028
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author Basner-Tschakarjan, Etiena
Bijjiga, Enoch
Martino, Ashley T.
author_facet Basner-Tschakarjan, Etiena
Bijjiga, Enoch
Martino, Ashley T.
author_sort Basner-Tschakarjan, Etiena
collection PubMed
description Transitioning to human trials from pre-clinical models resulted in the emergence of inhibitory AAV vector immune responses which has become a hurdle for sustained correction. Early animal studies did not predict the full range of host immunity to the AAV vector in human studies. While pre-existing antibody titers against AAV vectors has been a lingering concern, cytotoxic T-cell (CTL) responses against the input capsid can prevent long-term therapy in humans. These discoveries spawned more thorough profiling of immune response to rAAV in pre-clinical models, which have assessed both innate and adaptive immunity and explored methods for bypassing these responses. Many efforts toward measuring innate immunity have utilized Toll-like receptor deficient models and have focused on differential responses to viral capsid and genome. From adaptive studies, it is clear that humoral responses are relevant for initial vector transduction efficiency while cellular responses impact long-term outcomes of gene transfer. Measuring humoral responses to AAV vectors has utilized in vitro neutralizing antibody assays and transfer of seropositive serum to immunodeficient mice. Overcoming antibodies using CD20 inhibitors, plasmapheresis, altering route of delivery and using different capsids have been explored. CTL responses were measured using in vitro and in vivo models. In in vitro assays expansion of antigen-specific T-cells as well as cytotoxicity toward AAV transduced cells can be shown. Many groups have successfully mimicked antigen-specific T-cell proliferation, but actual transgene level reduction and parameters of cytotoxicity toward transduced target cells have only been shown in one model. The model utilized adoptive transfer of capsid-specific in vitro expanded T-cells isolated from immunized mice with LPS as an adjuvant. Finally, the development of immune tolerance to AAV vectors by enriching regulatory T-cells as well as modulating the response pharmacologically has also been explored.
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spelling pubmed-39167752014-02-25 Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors Basner-Tschakarjan, Etiena Bijjiga, Enoch Martino, Ashley T. Front Immunol Immunology Transitioning to human trials from pre-clinical models resulted in the emergence of inhibitory AAV vector immune responses which has become a hurdle for sustained correction. Early animal studies did not predict the full range of host immunity to the AAV vector in human studies. While pre-existing antibody titers against AAV vectors has been a lingering concern, cytotoxic T-cell (CTL) responses against the input capsid can prevent long-term therapy in humans. These discoveries spawned more thorough profiling of immune response to rAAV in pre-clinical models, which have assessed both innate and adaptive immunity and explored methods for bypassing these responses. Many efforts toward measuring innate immunity have utilized Toll-like receptor deficient models and have focused on differential responses to viral capsid and genome. From adaptive studies, it is clear that humoral responses are relevant for initial vector transduction efficiency while cellular responses impact long-term outcomes of gene transfer. Measuring humoral responses to AAV vectors has utilized in vitro neutralizing antibody assays and transfer of seropositive serum to immunodeficient mice. Overcoming antibodies using CD20 inhibitors, plasmapheresis, altering route of delivery and using different capsids have been explored. CTL responses were measured using in vitro and in vivo models. In in vitro assays expansion of antigen-specific T-cells as well as cytotoxicity toward AAV transduced cells can be shown. Many groups have successfully mimicked antigen-specific T-cell proliferation, but actual transgene level reduction and parameters of cytotoxicity toward transduced target cells have only been shown in one model. The model utilized adoptive transfer of capsid-specific in vitro expanded T-cells isolated from immunized mice with LPS as an adjuvant. Finally, the development of immune tolerance to AAV vectors by enriching regulatory T-cells as well as modulating the response pharmacologically has also been explored. Frontiers Media S.A. 2014-02-07 /pmc/articles/PMC3916775/ /pubmed/24570676 http://dx.doi.org/10.3389/fimmu.2014.00028 Text en Copyright © 2014 Basner-Tschakarjan, Bijjiga and Martino. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Basner-Tschakarjan, Etiena
Bijjiga, Enoch
Martino, Ashley T.
Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title_full Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title_fullStr Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title_full_unstemmed Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title_short Pre-Clinical Assessment of Immune Responses to Adeno-Associated Virus (AAV) Vectors
title_sort pre-clinical assessment of immune responses to adeno-associated virus (aav) vectors
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916775/
https://www.ncbi.nlm.nih.gov/pubmed/24570676
http://dx.doi.org/10.3389/fimmu.2014.00028
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