AAV-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.

中文翻译：

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AAV 基因治疗载体中 CpG 的存在在给药后很早就诱导出浆细胞样树突状细胞群

AAV 介导的基因转移是一个有前途的平台，但仍然受到潜在的宿主来源的、对治疗成分的拮抗免疫反应的困扰。 CpG 介导的 TLR9 刺激可激活先天免疫细胞，并导致同源 T 细胞激活并抑制转基因表达。在这里，我们证明，早在小鼠载体施用后 24 小时，CpG 耗尽就使抗体转基因产物的表达增加了 2-3 倍。在抗转基因产物/抗AAV衣壳抗体产生或细胞毒性基因诱导方面没有发现显着差异。相反，CpG 耗竭显着减少了 pDC 样骨髓细胞群的存在，该细胞群能够通过 Fc-FcγR 相互作用直接结合抗体转基因产物。因此，我们扩展了 AAV 基因治疗中 TLR9 介导的转基因表达拮抗机制，以包括先前未报道的 pDC 样细胞群的作用。