Immune Responses Limit Adenovirally Mediated Gene Expression in the Adult Mouse Eye
Abstract
In order to investigate the immunological consequences of gene transfer to the eye using viral vectors, adenovirus carrying a lacZ reporter gene (AV.LacZ) was injected either subretinally, subconjunctivally or into the anterior chamber of three groups of adult mice: immunocompetent or transiently immunosuppressed BALB/c mice and congenic immunodeficient nude mice. Adenovirally mediated lacZ expression persisted for approximately 3 weeks following injection of the vector into the anterior chamber, retina or extra ocular tissues of the conjuctiva of BALB/c mice. It appears that T cell-mediated immune responses limit the duration of AV-mediated ocular gene expression in adult mice since lacZ gene expression was detected for at least 15 weeks in T cell-deficient BALB/c nude mice, although the level of transgene expression decreased with time. Since intra-ocular AV-mediated gene expression was not significantly longer than extra-ocular expression, it appears that the eye is not normally immune-privileged with respect to viral vectors. Inflammatory cells were detected in the vitreous after anterior chamber injection and in the retina after subretinal injection of adenovirus. The presence of both CD4+ and CD8+ T cells was established by immunophenotyping. Reinjection of BALB/c mice resulted in rapid decline in reporter gene expression, but successful readministration was possible in the case of immunodeficient nude mice. However, after transient depletion of T cells, achieved by intraperitoneal injection of both CD8- and CD4-specific antibodies, the duration of expression in BALB/c mice was longer in the eye (at least 12 weeks, again with decrease in level over time), than in extra-ocular tissues (8 weeks) provided the animal was not reinjected with virus raising the possibility of partial ocular immune-privilege after transient immunosuppression.
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In mice injected with Ad carrying a lacZ reporter gene, CD4+ and CD8+ T-cell infiltration was observed in retinal sections, anti-Ad antibodies were measured in immunocompetent mice, and transgene expression decreased with time due to the immune response elicited by Ad; transient T-cell depletion prolonged expression but it was eliminated once depletion stopped.
“In order to investigate the immune consequences of Ad, three groups of adult mice were injected with Ad carrying a lacZ reporter gene into immunocompetent, transiently immunosuppressed BALB/c mice and congenital, immunodeficient nude mice.CD4 + and CD8 + T-cell infiltration was observed in retinal sections, and anti-Ad antibodies were also measured in the immunocompetent mice.The transgene”
From Immune responses to gene editing by viral and non-viral delivery vectors used in retinal gene therapy (2022) · cites this paper as [63]
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- Authors
- Reichel, M., Ali, R., Thrasher, A., Hunt, D., Bhattacharya, S., & Baker, D.
- Affiliations
- University College London (GB)
- ORCID
- Baker, D
- Venue
- Gene Therapy
- Published
- 1998-08-01
- Volume
- 5
- Issue
- 8
- Pages
- 1038-1046
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W2047633827
- Cited by
- 106
- References
- 34
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 4
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- adenoviral vector, immune privilege, T cell immunity, subretinal injection, anterior chamber injection, subconjunctival injection, nude mice, immunodeficient mice, transient immunosuppression, CD4+ T cells, CD8+ T cells, vitreous inflammation, ocular immunology
- MeSH terms
- Adenoviridae, Animals, Anterior Chamber, Antibodies, Antibodies, Viral, beta-Galactosidase, Blood-Retinal Barrier, Conjunctiva, Eye, Genetic Vectors, Immunosuppression Therapy, Injections, Retina, T-Lymphocytes, Time Factors, Transfection, Genetic Therapy, Gene Expression, Mice
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