The presence of CpGs in AAV gene therapy vectors induces a plasmacytoid dendritic cell-like population very early after administration

Cell Immunol. 2024 Mar 19;399-400:104823. doi: 10.1016/j.cellimm.2024.104823. Online ahead of print.ABSTRACTAAV-mediated gene transfer is a promising platform still plagued by potential host-derived, antagonistic immune responses to therapeutic components. CpG-mediated TLR9 stimulation activates innate immune cells and leads to cognate T cell activation and suppression of transgene expression. Here, we demonstrate that CpG depletion increased expression of an antibody transgene product by 2-3-fold as early as 24 h post-vector administration in mice. No significant differences were noted in anti-transgene product/ anti-AAV capsid antibody production or cytotoxic gene induction. Instead, CpG depletion significantly reduced the presence of a pDC-like myeloid cell population, which was able to directly bind the antibody transgene product via Fc-FcγR interactions. Thus, we extend the mechanisms of TLR9-mediated antagonism of transgene expression in AAV gene therapy to include the actions of a previously unreported pDC-like cell population.PMID:38520831 | DOI:10.1016/j.cellimm.2024.104823
Source: Cellular Immunology - Category: Allergy & Immunology Authors: Source Type: research