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• W2562271040 abstract "From animal experiments to the first human clinical trials in 2007, recombinant adeno-associated virus (rAAV)-mediated ocular gene therapy has shown successful results which have been attributed in part to the immune-privileged situation of the eye. Recently, some ocular gene therapy clinical trials have reported that visual acuity returned to baseline 6 to 12 months after therapy. The involvement of anti-transgene immune responses may lead to loss of therapeutic efficacy. This prompted us to evaluate in a murine model if rAAV gene transfer leads to the expected immune ignorance of the transgene or perhaps to an immuno-modulatory mechanism already described with subretinal peptide injection (eg. Anterior Chamber Associated Immune Deviation / ACAID), or to anti-transgene immunization. In this study, we characterized the CD4 and CD8 T cell responses specifically directed toward the transgene product in a murine model following rAAV2/8-mediated subretinal gene transfer. An rAAV2/8 encoding for the GFP-HY fusion protein under the phosphoglycerate kinase (PGK) promoter was used. The transgene expresses the HY male antigen which contains MHC class I and MHC class II-restricted T cell epitopes (UTY and DBY, respectively) that are immunodominant in female mice. For the study, 2µL of endotoxin-free, PBS-formulated rAAV2/8 PGK GFP-HY were injected subretinally in C57Bl/6 female mice. At day 7, mice were challenged subcutaneously with the UTY and DBY peptides adjuvanted in CFA, and the immune response was analyzed at day 14 by IFNγ ELISpot, cytokine titration and proliferation assays. Our results revealed that: (i) The subretinal injection of 10E8 to 2.10E9 vg/mouse of rAAV2/8 PGK GFP-HY did not induce a significant HY-specific peripheral immune modulation in contrast to the ACAID obtained after subretinal injection of UTY and DBY peptides (50µg each); (ii) Higher doses of rAAV2/8 PGK GFP-HY (5.10E10 vg/mouse) triggered increased Th1 and Tc1 cellular immune responses against the transgene product in peripheral lymphoid organs. Lower doses of vector did not increase peripheral immune responses toward the transgene product following the challenge. We have thus far failed to demonstrate the induction of ACAID by rAAV2/8 subretinal gene transfer. We show that rAAV2/8 vector-mediated subretinal gene transfer is not necessarily ignored at the immunological level. High doses of vector can effectively trigger anti-transgene T-cell responses with the potential for elimination of transgene-expressing cells. Clearly, anti-transgene-specific immune monitoring should be refined at least in preclinical models, to improve the biosafety and the long-term efficacy of rAAV-mediated ocular gene transfer." @default.
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• W2562271040 date "2016-05-01" @default.
• W2562271040 modified "2023-09-24" @default.
• W2562271040 title "694. Anti-Transgene Cellular Immune Repsonses Can Be Induced by Subretinal Gene Transfer with rAAV in a Dose-Dependent Manner" @default.
• W2562271040 doi "https://doi.org/10.1016/s1525-0016(16)33502-x" @default.
• W2562271040 hasPublicationYear "2016" @default.
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