Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector
Open accessAbstract
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 × 10 12 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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A recent study reported a loss of KCs due to necrosis/apoptosis following high-dose AAV administration, which could be a potential source of IL-1 cytokines.
“A recent study reported a loss of KCs due to necrosis/apoptosis following high-dose AAV administration, which could be a potential source of IL-1 cytokines.36”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [36]
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- Authors
- Carestia, A., Kim, S.-J., Horling, F., Rottensteiner, H., Lubich, C., Reipert, B. M., Crowe, B. A., & Jenne, C. N.
- Affiliations
- University of Calgary (CA)
- IMC University of Applied Sciences Krems (AT)
- Corresponding author
- Jenne, Craig N.
- ORCID
- Venue
- Molecular Therapy - Methods & Clinical Development
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 20
- Pages
- 95-108
- ISSN
- 2329-0501 (ISSN-L)
- PMC
- PMC7750493
- OpenAlex
- W3094893280
- Cited by
- 24
- References
- 39
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 3
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Baxalta Innovations GmbH
- Beverley Phillips Rising Star Postdoctoral Fellowship
- University of Calgary, Cumming School of Medicine Postdoctoral Scholar Program
- Canada Research Chairs Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- AAV8, gene therapy vectors, liver immune microenvironment, innate immune response, Kupffer cells, hepatocyte infection, platelet aggregation, neutrophil extracellular traps, monocyte recruitment, B cells, T cells, intravital microscopy, hepatocyte death, liver inflammation
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