title: Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression.
abstract: Recombinant adenoviruses containing the canine factor IX (FIX) cDNA were directly introduced in the hind leg muscle of mice. We show that (i) in nude mice, high expression (1-5 micrograms/ml in plasma) of FIX protein can be detected for > 300 days; (ii) in contrast, expression of FIX protein was transient (7-10 days) in normal mice; (iii) CD8+ lymphocytes could be detected within 3 days in the infected muscle tissue; (iv) use of beta 2-microglobulin and immunoglobulin M heavy chain "knockout" mice showed that lack of sustained expression of FIX protein is due to cell-mediated and humoral immune responses; (v) normal mice, once infected with recombinant adenovirus, could not be reinfected efficiently for at least 30 days due to neutralizing viral antibodies; and, finally, (vi) using immunosuppressive drugs, some normal mice can be tolerized to produce and secrete FIX protein for > 5 months. We conclude that currently available adenoviral vectors have serious limitations for use for long-term gene therapy.
authors.affiliation: Molecular Biology and Virology Laboratory, Salk Institute, San Diego, CA 92186-5800.
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.forename: E M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: D
authors.initials: D
authors.lastname: Gu
authors.forename: W W
authors.initials: WW
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Sarvetnick
authors.forename: I M
authors.initials: IM
authors.lastname: Verma
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation; D000956:Antigens, Viral / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D005164:Factor IX / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007108:Immune Tolerance; D007111:Immunity, Cellular; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D014764:Viral Proteins / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D014764:Viral Proteins; D016572:Cyclosporine; D003520:Cyclophosphamide; D005164:Factor IX