title: Generation and in vivo evaluation of IL10-treated dendritic cells in a nonhuman primate model of AAV-based gene transfer.
abstract: 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.
authors.affiliation: INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes , Nantes, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Moreau
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Vandamme
authors.affiliation: INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes , Nantes, France.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Segovia
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Devaux
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guilbaud
authors.affiliation: INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes , Nantes, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Tilly
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jaulin
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Le Duff
authors.affiliation: ONIRIS, INRA UMR 703/Atlantic Gene Therapies , Nantes, France.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cherel
authors.affiliation: ONIRIS, INRA UMR 703/Atlantic Gene Therapies , Nantes, France.
authors.forename: Jack-Yves
authors.initials: JY
authors.lastname: Deschamps
authors.affiliation: INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes , Nantes, France.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France ; Department of Molecular Genetics and Microbiology, University of Florida , Gainesville, Florida, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.affiliation: INSERM UMR 1064, ITUN - Institut de Transplantation Urologie Nephrologie, CHU de Nantes, Center of Research in Transplantation and Immunology, Université de Nantes , Nantes, France.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Cuturi
authors.affiliation: INSERM UMR 1089/Atlantic Gene Therapies, CHU de Nantes/Université de Nantes , Nantes, France.
authors.forename: Oumeya
authors.initials: O
authors.lastname: Adjali