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 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 beta-galactosidase-expressing virus (Ad-betagal), whereas T cell infiltrates were not detected after local delivery of Ad-FasL. Prior immunization prevented beta-galactosidase expression from Ad-betagal, whereas the expression of the FasL transgene was unaffected. When Ad-betagal and Ad-FasL were delivered together to preimmunized animals, T cell infiltration was reduced and beta-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.
Sata
M
M
Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA.
Perlman
H
H
Muruve
D A
DA
Silver
M
M
Ikebe
M
M
Libermann
T A
TA
Oettgen
P
P
Walsh
K
K
D000257:Adenoviridae Infections / Q000473:pathology*; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000293:injuries / Q000473:pathology; D053222:Fas Ligand Protein; D018014:Gene Transfer Techniques; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology*; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000293:injuries / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor