TLR9 信号转导介导系统性 AAV 基因治疗后的适应性免疫。
TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy.
机构信息
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Gene Therapy Program, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
出版信息
Cell Immunol. 2019 Dec;346:103997. doi: 10.1016/j.cellimm.2019.103997. Epub 2019 Oct 26.
An ongoing concern of in vivo gene therapy is adaptive immune responses against the protein product of a transgene, particularly for recessive diseases in which antigens are not presented to lymphocytes during central tolerance induction. Here we show that Toll-like receptor 9 (TLR9) signaling activates T cells against an epitope tagged mitochondria-targeted ornithine transcarbamylase (OTC) following the administration of a systemic adeno-associated virus (AAV) vector. Using a transgenic mouse model system, we demonstrate that TLR9 signaling extrinsic to T cells induces a robust cytotoxic T-cell response against the transgene and results in transgene expression loss. Overall, our results suggest that inflammation mediated by TLR9 signaling and the presence of high affinity transgene-specific T cells is important for the development of adaptive immune responses to transgene products following AAV gene therapy.
体内基因治疗的一个持续关注的问题是针对转基因蛋白产物的适应性免疫反应，特别是对于在中枢耐受诱导期间不向淋巴细胞呈递抗原的隐性疾病。在这里，我们表明 Toll 样受体 9（TLR9）信号转导在给予系统性腺相关病毒（AAV）载体后，可激活针对带有表位标签的靶向线粒体的鸟氨酸转氨甲酰酶（OTC）的 T 细胞。使用转基因小鼠模型系统，我们证明了 T 细胞外在的 TLR9 信号转导可诱导针对转基因的强大细胞毒性 T 细胞反应，并导致转基因表达丧失。总体而言，我们的结果表明，TLR9 信号介导的炎症和高亲和力转基因特异性 T 细胞的存在对于 AAV 基因治疗后针对转基因产物的适应性免疫反应的发展很重要。
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