Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: Tolerization of factor IX and vector antigens allows for long-term expression

Yifan Dai, Edward M. Schwarz, Danling Gu, Wei Wei Zhang, Nora Sarvetnick, Inder M. Verma

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564 Scopus citations

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 μg/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 β2-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.

Original languageEnglish (US)
Pages (from-to)1401-1405
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number5
DOIs
StatePublished - Feb 28 1995

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