PREVENTION OF IMMUNE-REACTIONS TRIGGERED BY FIRST-GENERATION ADENOVIRAL VECTORS BY MONOCLONAL-ANTIBODIES AND CTLA4IG

The therapeutic potential of adenovirus-mediated gene transfer using f irst-generation vectors is severely limited by the fact that only tran sient expression is achievable in immunocompetent animals, The loss in transgene expression can be attributed at least in part to the appear ance of detrimental immune responses directed toward vector and/or tra nsgene-encoded determinants, FK506 and cyclosporin A both reduced thes e immune responses, These immunosuppressants, however, may induce many severe side effects during prolonged use, An alternative strategy has been developed to overcome these problems following in vivo transfect ion of muscles of adult immunocompetent mice with a Delta E(1)/E(3)(a) adenoviral vector encoding a beta-galactosidase (beta-Gal) expression cassette, YTS 177 (an anti-CD4 monoclonal antibody) as well as CTLA4I g, a recombinant protein, partially controlled the immune responses, T hey mere indeed able to reduce the muscle infiltration by CD4(+) and C D8(+) cells but they failed to repress the humoral response, Co-admini stration of YTS 191 (an anti-CD4), YTS 169 (an anti-CD8), and TIE 213 (an anti-CD11a) was, however, very efficient in blocking both cellular and humoral immune reactions, This combination of monoclonal antibodi es allowed strong and stable transgene expression over 1 month, These data underline the potential of monoclonal antibodies as immunosuppres sive adjunct treatment for adenovirus-mediated gene transfer.