Adenovirus-mediated delivery of Fas ligand inhibits intimal hyperplasia after balloon injury in immunologically primed animals

Background-Adenoviral constructs have been used for studies of injury-induc ed vascular hyperplasia in immunologically naive laboratory animals, but th eir usefulness for intra-arterial gene therapy may be limited by the preval ence of preexisting immunity to adenovirus in the patient population. Hen, we explored the efficacy of adenovirus-mediated transfer of Fns ligand, a c ytotoxic gene with immunomodulatory properties, in inhibiting injury-induce d vascular lesion formation in both naive and immunologically primed animal s. Methods and Results-Lesion formation was evaluated in balloon-injured carot id arteries of naive and adenovirus-immunized rats that were infected with adenoviral constructs expressing Fas ligand (Ad-FasL), the cyclin-dependent kinase inhibitor p21 (Ad-p21), or beta-galactosidase (Ad-beta gal). In nai ve rats, Ad-Fast induced apoptosis in medial vascular smooth muscle cells a nd inhibited intimal hyperplasia by 60% relative to Ad-beta gal-treated ves sels (P<0.05), whereas the cytostatic agent Ad-p21 decreased lesion size by 58% (P<0.05). In animals preimmunized with an adenoviral vector containing no transgene, Ad-Fast significantly inhibited neointima formation (73% red uction, P<0.05), but Ad-p21 failed to inhibit neointima formation relative to controls. Immunologically primed rats displayed robust T-cell infiltrati on in Ad-p21- and Ad-beta gal-treated vessels, but T-cell infiltration was markedly attenuated in Ad-Fast-treated vessels. Conclusions-Our data demonstrate that adenovirus-mediated Fas ligand delive ry can inhibit intimal hyperplasia in both immunologically primed and naive animals, whereas the efficacy of an adenovirus-mediated p21 delivery is li mited to immunologically naive animals. This study documents, for the first time, the therapeutic efficacy of intravascular adenoviral gene transfer i n animals with preexisting immunity to adenovirus.