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 (Fast) 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 Fast (Ad-Fast) 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-Fast 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-beta gal), whereas T cell infiltrates were not detected after local delivery of Ad-Fast, Prior immunization prevented beta-galactosidase expression from Ad-beta gal, whereas the expression of the Fast transgene was unaffected, When Ad-beta gal and Ad-Fast were delivered together to preimmunized animals, T cell infiltration was reduced and beta-galactosidase expression was restored, These data demonstrate that Pas ligand gene transfer can effectively inhibit injury-induced vessel lesion formation and can allow adenovirus-harboring cells to evade immune destruction.