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Article Dans Une Revue JCI Insight Année : 2019

Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

Résumé

Immune responses to therapeutic transgenes are a potential hurdle to treat monogenic muscle disorders. These responses result from the neutralizing activity of transgene-specific B cells and cytotoxic T cells recruited upon gene transfer. We explored here how dual muscle-liver expression of a foreign transgene allows muscle transgene engraftment after adenoassociated viral vector delivery. We found in particular that induction of transgene-specific tolerance is imposed by concurrent muscle and liver targeting, resulting in the absence of CD8+ T cell responses to the transgene. This tolerance can be temporally decoupled, because transgene engraftment can be achieved in muscle weeks after liver transduction. Importantly, transgene-specific CD8+ T cell tolerance can be established despite preexisting immunity to the transgene. Whenever preexisting, transgene-specific CD4+ and CD8+ memory T cell responses are present, dual muscle-liver transduction turns polyclonal, transgene-specific CD8+ T cells into typically exhausted T cells with high programmed cell death 1 (PD-1) expression and lack of IFN-γ production. Our results demonstrate that successful transduction of muscle tissue can be achieved through liver-mediated control of humoral and cytotoxic T cell responses, even in the presence of preexisting immunity to the muscle-associated transgene.

Dates et versions

hal-02332827 , version 1 (25-10-2019)

Identifiants

Citer

Laurent Bartolo, Stéphanie Li Chung Tong, Pascal Chappert, Dominique Urbain, Fanny Collaud, et al.. Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity. JCI Insight, 2019, 4 (11), pii: 127008. ⟨10.1172/jci.insight.127008⟩. ⟨hal-02332827⟩
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