title: Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung.
abstract: Sendai virus (SeV) is able to transfect airway epithelial cells efficiently in vivo. However, as with other viral vectors, repeated administration leads to reduced gene expression. We have investigated the impact of inducing immunological tolerance to immunodominant T-cell epitopes on gene expression following repeated administration. Immunodominant CD4 and CD8 T-cell peptide epitopes of SeV were administered to C57BL/6 mice intranasally 10 days before the first virus administration with transmission-incompetent F-protein-deleted DeltaF/SeV-GFP. At 21 days after the first virus administration, mice were again transfected with DeltaF/SeV. To avoid interference of anti-GFP antibodies, the second transfection was carried out with DeltaF/SeV-lacZ. At 2 days after the final transfection lung beta-galactosidase expression, T-cell proliferation and antibody responses were measured. A state of 'split tolerance' was achieved with reduced T-cell proliferation, but no impact on antiviral antibody production. There was no enhancement of expression on repeat administration; instead, T-cell tolerance was, paradoxically, associated with a more profound extinction of viral expression. Multiple immune mechanisms operate to eradicate viruses from the lung, and these findings indicate that impeding the adaptive T-cell response to the immunodominant viral epitope is not sufficient to prevent the process.
authors.affiliation: Department of Gene Therapy, NHLI, Imperial College, Edinburgh, London, UK. u.griesenbach@imperial.ac.uk
authors.forename: U
authors.initials: U
authors.lastname: Griesenbach
authors.forename: R J
authors.initials: RJ
authors.lastname: Boyton
authors.forename: L
authors.initials: L
authors.lastname: Somerton
authors.forename: S E
authors.initials: SE
authors.lastname: Garcia
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: T
authors.initials: T
authors.lastname: Owaki
authors.forename: Z
authors.initials: Z
authors.lastname: Ya-Fen
authors.forename: D M
authors.initials: DM
authors.lastname: Geddes
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.forename: D M
authors.initials: DM
authors.lastname: Altmann
authors.forename: E W F W
authors.initials: EW
authors.lastname: Alton
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D007108:Immune Tolerance / Q000235:genetics; D016056:Immunodominant Epitopes / Q000276:immunology; D008168:Lung / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D029082:Sendai virus / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D016056:Immunodominant Epitopes; D014765:Viral Vaccines