Fas Ligand Gene Transfer to the Vessel Wall Inhibits Neointima Formation and Overrides the Adenovirus-Mediated T Cell Response

Proliferation of vascular smooth muscle cells (VSMCs) in response to injury plays a key role in the pathogenesis of vascular disorders. Fas ligand (FasL) induces apoptosis in Fas-bearing cells, and its expression on activated T cells contributes to the regulation of the immune response and physiolog...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-02, Vol.95 (3), p.1213-1217
Main Authors: Sata, Masataka, Perlman, Harris, Muruve, Daniel A., Silver, Marcy, Ikebe, Mitsuo, Libermann, Towia A., Oettgen, Peter, Walsh, Kenneth
Format: Article
Language:English
Subjects:
Adenoviridae Infections - pathology
Adenoviruses
Angioplasty, Balloon - adverse effects
Animals
Apoptosis
Arteries
Biological Sciences
Carotid arteries
Cells
Cellular biology
DNA Fragmentation
Endothelium, Vascular - injuries
Endothelium, Vascular - pathology
Fas Ligand Protein
fas Receptor - genetics
fas Receptor - immunology
Gene Transfer Techniques
Genes
Humans
Immune system
Infections
Jurkat Cells
Lesions
Ligands
Male
Membrane Glycoproteins - genetics
Membrane Glycoproteins - immunology
Muscle, Smooth, Vascular - immunology
Muscle, Smooth, Vascular - injuries
Muscle, Smooth, Vascular - pathology
Physical trauma
Rats
Rats, Sprague-Dawley
T lymphocytes
T-Lymphocytes - immunology
T-Lymphocytes - virology
Transgenes
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Summary:Proliferation of vascular smooth muscle cells (VSMCs) in response to injury plays a key role in the pathogenesis of vascular disorders. Fas ligand (FasL) induces apoptosis in Fas-bearing cells, and its expression on activated T cells contributes to the regulation of the immune response and physiological cell turnover. Here, we show that a replication-defective adenovirus encoding FasL (Ad-FasL) induced apoptosis in Fas-bearing VSMCs. When introduced locally to balloon-injured rat carotid arteries, a well characterized model of a VSMC-derived lesion, Ad-FasL functioned as a potent inhibitor of neointima formation. In rats immunized with an empty adenoviral vector, robust T cell infiltration of the vessel wall was detected after local delivery of a β -galactosidase-expressing virus (Ad-β gal), whereas T cell infiltrates were not detected after local delivery of Ad-FasL. Prior immunization prevented β -galactosidase expression from Ad-β gal, whereas the expression of the FasL transgene was unaffected. When Ad-β gal and Ad-FasL were delivered together to preimmunized animals, T cell infiltration was reduced and β -galactosidase expression was restored. These data demonstrate that Fas ligand gene transfer can effectively inhibit injury-induced vessel lesion formation and can allow adenovirus-harboring cells to evade immune destruction.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.3.1213