Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung

• Published in: Gene therapy Vol. 13; no. 5; pp. 449 - 456
• Main Authors: GRIESENBACH, U, BOYTON, R. J, ALTON, E. W. F. W, SOMERTON, L, GARCIA, S. E, FERRARI, S, OWAKI, T, YA-FEN, Z, GEDDES, D. M, HASEGAWA, M, ALTMANN, D. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.03.2006
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; CD4 antigen; CD4 Antigens - immunology; CD8 antigen; CD8 Antigens - immunology; Cell growth; Cell Proliferation; Epithelial cells; Epitopes; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Genetic Engineering; Genetic Therapy - methods; Health. Pharmaceutical industry; Immune Tolerance - genetics; Immunodominant Epitopes - immunology; Immunological tolerance; Industrial applications and implications. Economical aspects; Kinases; Lung - immunology; Lungs; Lymphocytes T; Medical sciences; Mice; Mice, Inbred C57BL; Paramyxoviruses; Physiological aspects; Sendai virus; Sendai virus - genetics; Sendai virus - immunology; T cells; T-Lymphocytes - immunology; Transfection; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Viral Vaccines - administration & dosage; Viral Vaccines - immunology; Viruses; β-Galactosidase; United Kingdom; Antigenic determinant; Induction; Sendai virus; Lung; Tolerance; Gene expression; T cells; Respiratory system; Paramyxoviridae; Virus; Paramyxovirinae; Mononegavirales; tolerization; Gene therapy; Paramyxovirus
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302677

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.