Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer.

A Moreau (1) , C Vandamme (2) , Mercedes Segovia (3) , M. Devaux (2) , Mickaël Guilbaud (2) , Gaëlle Tilly (3) , Nicolas Jaulin (2) , Johanne Le Duff (2) , Yan Cherel (4) , Jack-Yves Deschamps (4) , Ignacio Anegon (3) , Philippe Moullier (2) , Maria Cristina Cuturi (3) , Oumeya Adjali (2)

1 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
2 Inserm UMR 1089 - Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques
3 UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie
4 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux

Preventing untoward immune responses against a specific antigen is a major challenge in different clinical settings such as gene therapy, transplantation, or autoimmunity. Following intramuscular delivery of recombinant adeno-associated virus (rAAV)-derived vectors, transgene rejection can be a roadblock to successful clinical translation. Specific immunomodulation strategies potentially leading to sustained transgene expression while minimizing pharmacological immunosuppression are desirable. Tolerogenic dendritic cells (TolDC) are potential candidates but have not yet been evaluated in the context of gene therapy, to our knowledge. Following intramuscular delivery of rAAV-derived vectors expressing an immunogenic protein in the nonhuman primate model, we assessed the immunomodulating potential of autologous bone marrow-derived TolDC generated in the presence of IL10 and pulsed with the transgene product. TolDC administered either intradermally or intravenously were safe and well tolerated. While the intravenous route showed a modest ability to modulate host immunity against the transgene product, intradermally delivery resulted in a robust vaccination of the macaques when associated to intramuscular rAAV-derived vectors-based gene transfer. These findings demonstrate the critical role of TolDC mode of injection in modulating host immunity. This study also provides the first evidence of the potential of TolDC-based immunomodulation in gene therapy.

Domaines: Immunologie; Médecine humaine et pathologie

A Moreau, C Vandamme, Mercedes Segovia, M. Devaux, Mickaël Guilbaud, et al.. Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer.. Mol Ther Methods Clin Dev, 2014, 1. ⟨hal-01222897⟩