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Communication dans un congrès Année : 2019

Concurrent Muscle and Liver Transduction Imposes Immune Tolerance for Muscle rAAV Gene Transfer

L Bartolo
  • Fonction : Auteur
D A Gross
  • Fonction : Auteur
P Chappert
  • Fonction : Auteur
J Demengeot
  • Fonction : Auteur
F Mingozzi
  • Fonction : Auteur

Résumé

Reaching long term immune tolerance to therapeutic transgenes represents an important goal for gene therapists, particularly for the treatment of monogenic muscular pathologies, such as Duchenne muscular dystrophy. Indeed, when the transgene contains sequence elements divergent from endogenous ones, a collection of lymphocytes that have not been purged during their development is available to initiate rejection of transduced cells. The ensuing recruitment and activation of transgene-specific lymphocytes generates adverse humoral and cellular responses, which are prominent in tissues subjected to vector transduction and inflammation. To overcome this obstacle, we harnessed the tolerogenic properties of the liver and explored how dual muscle-liver expression of a foreign transgene allows muscle transgene engraftment. We found that concurrent rAAV transduction of muscle and liver promotes a state of transgene-specific tolerance, resulting in the absence of CD8+ T cell responses combined with lower humoral response to the transgene. This tolerance is achievable in muscle weeks after liver transduction and is equally able to override preexisting immunity to the transgene. Regarding the mechanism, we found that dual muscle-liver transduction converts preexisting polyclonal, transgene-specific CD8+ T cells into typically exhausted T cells with high programmed cell death 1 expression and low IFN-γ production. Our results complemented with muscle confocal imaging demonstrate that transduction of muscle tissue can be protected from immune attack by liver-mediated control of humoral and cytotoxic T cell responses. Importantly, this liver-based tolerance induction process applies even in the presence of preexisting immunity to the transgene of interest.
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Dates et versions

hal-02397459, version 1 (06-12-2019)

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  • HAL Id : hal-02397459 , version 1

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L Bartolo, D A Gross, P Chappert, J Demengeot, F Mingozzi, et al.. Concurrent Muscle and Liver Transduction Imposes Immune Tolerance for Muscle rAAV Gene Transfer. ESGCT 27th Congress, Oct 2019, Barcelonne, Spain. ⟨hal-02397459⟩
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