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Gene therapy: Advances and limitations
Author(s) -
Ascher Nancy L.
Publication year - 1996
Publication title -
liver transplantation and surgery
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1074-3022
DOI - 10.1002/lt.500020513
Subject(s) - biology , ctl* , genetic enhancement , cytotoxic t cell , major histocompatibility complex , recombinant dna , adenoviridae , virology , immunotherapy , viral vector , immune system , immunology , gene , in vitro , cd8 , genetics
Recombinant adenovirus vectors are efficient at transferring genes into somatic tissues but are limited for use in clinical gene therapy by immunologic factors that result in the rapid loss of gene expression and inhibit secondary gene transfer. This study demonstrates that systemic coadministration of recombinant adenovirus with soluble CTLA4lg, which is known to block co‐stimulatory signals between T cells and antigen presenting cells, leads to persistent adenovirus gene expression in mice without long‐term immunosuppression. This form of immunotherapy greatly enhances the likelihood that recombinant adenovirus vectors will be useful for human gene therapy. Recombinant adenoviruses are attractive vehicles for liver‐directed gene therapy because of the high efficiency with which they transfer genes to hepatocytes in vivo. First‐generation recombinant adenoviruses deleted of E1 sequences also express recombinant and early and late viral genes, which lead to development of destructive cellular immune responses. Previous studies indicated that class I major histocompatibility complex (MHC)‐restricted cytotoxic T lymphocytes (CTLs) play a major role in eliminating virusinfected cells. The present studies utilize mouse models to evaluate the role of T‐helper cells in the primary response to adenovirus‐mediated gene transfer to the liver. In vivo ablation of CD4+ cells or interferon γ (INF‐γ) was sufficient to prevent the elimination of adenovirus‐transduced hepatocytes, despite the induction of a measurable CTL response. Mobilization of an effective T H1 response as measured by in vitro proliferation assays was associated with substantial upregulation of MHC class I expression, an effect that was prevented in IFN‐γ‐deficient animals. These results suggest that elimination of virus‐infected hepatocytes in a primary exposure to recombinant adenovirus requires both induction of antigen‐specific CTLs as well as sensitization of the target cell by the T H1 ‐mediated activation of MHC class I expression.