TRANSIENT IMMUNOMODULATION WITH ANTI-CD40 LIGAND ANTIBODY AND CTLA4IGENHANCES PERSISTENCE AND SECONDARY ADENOVIRUS-MEDIATED GENE-TRANSFER INTO MOUSE-LIVER

Although recombinant adenovirus vectors offer a very efficient means b y which to transfer genetic information into cells in vivo, antigen-de pendent immunity limits the duration of gene expression sand prevents retreatment. Recombinant murine CTLA4Ig and anti-CD40 ligand antibody block costimulatory interactions between T cells and antigen presentin g cells. We previously reported that murine CTLA4Ig prolongs adenovira l-mediated gene transfer, hut does not allow for secondary expression after readministration of the vector, In studies described here, when anti-CD40 ligand and recombinant murine CTLA4Ig were coadministered ar ound the time of primary vector administration (i) prolonged adenoviru s-mediated gene expression (length of experiment up to 1 veer) from th e livers of >90% of treated mice Tvas observed, and (ii) secondary ade novirus-mediated gene transfer a as achieved in >50% of the mice even after the immunosuppressive effects of these agents were no longer pre sent, Nearly two-thirds of these mice had persistent secondary gene ex pression lasting for at least 200-300 days. Neither agent alone allowe d transduction after secondary vector administration, Treated mice had decreased immune responses to the vector as shown by markedly decreas ed production of neutralizing antibodies, diminished spleen proliferat ion responses and IFN-gamma production in vitro, and reduced T cell in filtrates in the liver. These results suggest that it may be possible to obtain persistence as well as secondary adenoviral-mediated gene tr ansfer with transient immunosuppressive therapies.