Oral-tolerization Prevents Immune Responses and Improves Transgene Persistence Following Gene Transfer Mediated by Adeno-associated Viral Vector.
Gene therapy represents a feasible strategy to treat inherited monogenic diseases and intramuscular (i.m.) injection of recombinant adeno-associated viral (AAV) vector is now recognized as a convenient and safe method of gene transfer. However, this approach is hampered by immune responses directed against the vector and against the transgenic protein. We used here to reproduce this situation a mouse model where robust immune responses are induced following injection of an AAV vector coding for an immunogenic transgenic protein. We show that prophylactic oral administration of the immunogenic protein before AAV-mediated gene transfer completely prevented antibody formation and cytotoxic CD8(+) T-cell response. Consistently, prophylactic oral-tolerization considerably improved long-term transgene persistence and expression. Mechanistically, inhibition of the cytotoxic immune response involved abortive proliferation of antigen-specific cytotoxic CD8(+) T cells, upregulation of the PD-1 immunoregulatory molecule, downregulation of the Bcl-2 antiapoptotic factor, and their deletion in the context of AAV-mediated gene transfer. Hence, gene therapy may represent an ideal situation where oral-tolerization can be adopted before or at the same time as vector injection to efficiently prevent deleterious immune responses directed against the transgenic protein.
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Romain
R
Hardet
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Benjamin
B
Chevalier
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Léa
L
Dupaty
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Yassine
Y
Naïmi
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Gaëtan
G
Riou
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Laurent
L
Drouot
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Laetitia
L
Jean
International Center for Research in Infectiology (CIRI), Inserm U1111, CNRS UMR5308, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université de Lyon, UCB-Lyon1, Lyon, France.|LabEx Ecofect, Université de Lyon, Lyon, France.
Anna
A
Salvetti
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.|Rouen University Hospital, Department of Immunology, Rouen, France.
Olivier
O
Boyer
Inserm, U905, Rouen, France.|Normandie University, Institute for Research and Innovation in Biomedicine, Rouen, France.
Sahil
S
Adriouch
D000284:Administration, Oral; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D007108:Immune Tolerance; D007273:Injections, Intramuscular; D051379:Mice; D010047:Ovalbumin / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism
D061026:Programmed Cell Death 1 Receptor; D010047:Ovalbumin