Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector.
Mol Ther Methods Clin Dev
; 20: 95-108, 2021 Mar 12.
Article
em En
| MEDLINE
| ID: mdl-33376758
ABSTRACT
Adeno-associated viruses (AAVs) are emerging as one of the vehicles of choice for gene therapy. However, the potential immunogenicity of these vectors is a major limitation of their use, leading to the necessity of a better understanding of how viral vectors engage the innate immune system. In this study, we demonstrate the immune response mediated by an AAV vector in a mouse model. Mice were infected intravenously with 4 × 1012 copies (cp)/kg of AAV8, and the ensuing immune response was analyzed using intravital microscopy during a period of weeks. Administration of AAV8 resulted in the infection of hepatocytes, and this infection led to a moderate, but significant, activation of the immune system in the liver. This host immune response involved platelet aggregation, neutrophil extracellular trap (NET) formation, and the recruitment of monocytes, B cells, and T cells. The resident liver macrophage population, Kupffer cells, was necessary to initiate this immune response, as its depletion abrogated platelet aggregation and NET formation and delayed the recruitment of immune cells. Moreover, the death of liver cells produced by this AAV was moderate and failed to result in a robust, sustained inflammatory response. Altogether, these data suggest that AAV8 is a suitable vector for gene therapy approaches.
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1
Base de dados:
MEDLINE
Tipo de estudo:
Risk_factors_studies
Idioma:
En
Revista:
Mol Ther Methods Clin Dev
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Canadá