Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.03110
Keywords
AAV; gene therapy; immune response; CD8(+) T lymphocytes; tetramer-associated magnetic enrichment
Categories
Funding
- Inserm
- French Ministry of Research
- FRM (Fondation pour la Recherche Medicale)
- University Hospital of Nantes
- Fondation pour la Therapie Genique en Pays de Loire
- AFM-Telethon (Association Francaise contre les Myopathies)
- Region Pays de Loire (IMBIO-DC consortium)
- IHU-CESTI/the French National Research Agency (ANR) via the Investment Into The Future program [ANR-10-IBHU-005]
- UPGRADE H2020 Consortium [825825]
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Pre-existing immunity to AAV capsid may compromise the safety and efficiency of rAAV-mediated gene transfer in patients. Anti-capsid cytotoxic immune responses have proven to be a challenge to characterize because of the scarcity of circulating AAV-specific CD8(+) T lymphocytes which can seldom be detected with conventional flow cytometry or ELISpot assays. Here, we used fluorescent MHC class I tetramers combined with magnetic enrichment to detect and phenotype AAV8-specific CD8(+) T cells in human PBMCs without prior amplification. We showed that all healthy individuals tested carried a pool of AAV8-specific CD8(+) T cells with a CD45RA(+) CCR7(-) terminally-differentiated effector memory cell (T-EMRA) fraction. Ex vivo frequencies of total AAV-specific CD8(+) T cells were not predictive of IFN gamma ELISpot responses but interestingly we evidenced a correlation between the proportion of T-EMRA cells and IFN gamma ELISpot positive responses. T-EMRA cells may then play a role in recombinant AAV-mediated cytotoxicity in patients with preexisting immunity. Overall, our results encourage the development of new methods combining increased detection sensitivity of AAV-specific T cells and their poly-functional assessment to better characterize and monitor AAV capsid-specific cellular immune responses in the perspective of rAAV-mediated clinical trials.
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