Prolongation of adenoviral transgene expression in mouse liver by T lymphocyte subset depletion

• Published in: Gene therapy Vol. 3; no. 1; p. 4
• Main Authors: DeMatteo, R P, Markmann, J F, Kozarsky, K F, Barker, C F, Raper, S E
• Format: Journal Article
• Language: English
• Published: England 01.01.1996
• Subjects: Adenoviruses, Human - genetics; Adenoviruses, Human - immunology; Animals; Antibodies, Viral - blood; Antibody Formation; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Division - immunology; Cell Line; Cells, Cultured; Gene Expression; Gene Transfer Techniques; Genetic Vectors - genetics; Genetic Vectors - immunology; HeLa Cells; Humans; Lac Operon; Liver - metabolism; Lymph Nodes - cytology; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Thymectomy; Time Factors
• ISSN: 0969-7128; 1476-5462

Although first generation recombinant adenoviruses are efficient vehicles for gene transfer, their immunogenicity precludes long-term persistence. We show that adenoviral transgene expression in the liver of normal mice is prolonged from a baseline of less than 2 weeks to 7 weeks by depleting CD4+ T lymphocytes with thymectomy and a 3-day course of anti-CD4 monoclonal antibody or by nonselectively depleting T cells with a single dose of anti-thymocyte serum (ATS). Transgene expression persisted despite the development of an antiviral humoral immune response by 3 weeks after virus administration. In vitro assays of T lymphocyte function revealed an initial diminished capacity to proliferate in the presence of adenoviral antigens in animals depleted of CD4+ T cells or given anti-thymocyte serum. Eventual loss of recombinant gene expression coincided with the development of adenovirus-specific cytotoxic T lymphocyte activity in vitro. Immunosuppression provides a useful experimental tool to elucidate the immunobiology of recombinant adenoviruses and may have clinical application to adenovirus-mediated gene therapy.