TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy.

TLR9 signaling mediates adaptive immunity following systemic AAV gene therapy. Cell Immunol. 2019 Dec;346:103997 Authors: Ashley SN, Somanathan S, Giles AR, Wilson JM Abstract 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. PMID: 31703913 [PubMed - in process]
Source: Cellular Immunology - Category: Allergy & Immunology Authors: Tags: Cell Immunol Source Type: research

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