Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
Article Dans Une Revue JCI Insight Année : 2019

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

Laurent Bartolo
  • Fonction : Auteur
Stéphanie Li Chung Tong
  • Fonction : Auteur
Pascal Chappert
Dominique Urbain
  • Fonction : Auteur
Fanny Collaud
Pasqualina Colella
Isabelle Richard
Jocelyne Demengeot
David Gross
Federico Mingozzi
Jean Davoust
  • Fonction : Auteur

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.
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Dates et versions

hal-04324422 , version 1 (03-09-2024)

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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-04324422⟩
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