Prolongation of adenoviral transgene expression in mouse liver by T lymphocyte subset depletion.
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.
DeMatteo
R P
RP
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia, USA.
Markmann
J F
JF
Kozarsky
K F
KF
Barker
C F
CF
Raper
S E
SE
D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D013934:Thymectomy; D013997:Time Factors
D000914:Antibodies, Viral