| Autor: |
Jérôme Poupiot, Helena Costa Verdera, Romain Hardet, Pasqualina Colella, Fanny Collaud, Laurent Bartolo, Jean Davoust, Peggy Sanatine, Federico Mingozzi, Isabelle Richard, Giuseppe Ronzitti |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Molecular Therapy: Methods & Clinical Development, Vol 15, Iss , Pp 83-100 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2329-0501 |
| DOI: |
10.1016/j.omtm.2019.08.012 |
| Popis: |
The pro-tolerogenic environment of the liver makes this tissue an ideal target for gene replacement strategies. In other peripheral tissues such as the skeletal muscle, anti-transgene immune response can result in partial or complete clearance of the transduced fibers. Here, we characterized liver-induced transgene tolerance after simultaneous transduction of liver and muscle. A clinically relevant transgene, α-sarcoglycan, mutated in limb-girdle muscular dystrophy type 2D, was fused with the SIINFEKL epitope (hSGCA-SIIN) and expressed with adeno-associated virus vectors (AAV-hSGCA-SIIN). Intramuscular delivery of AAV-hSGCA-SIIN resulted in a strong inflammatory response, which could be prevented and reversed by concomitant liver expression of the same antigen. Regulatory T cells and upregulation of checkpoint inhibitor receptors were required to establish and maintain liver-mediated peripheral tolerance. This study identifies the fundamental role of the synergy between Tregs and upregulation of checkpoint inhibitor receptors in the liver-mediated control of anti-transgene immunity triggered by muscle-directed gene transfer. Keywords: AAV, gene transfer, liver, peripheral tolerance, checkpoint inhibitors, Tregs, PD-1, LAG3 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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