An immunomodulatory procedure that stabilizes transgene expression and permits readministration of E1-deleted adenovirus vectors

Immune responses against E1-deleted adenovirus vectors and/or their transge ne products result in the rapid elimination of vector-transduced cells and the generation of neutralizing antibodies. Different strategies of immunomo dulation to stabilize transgene expression at therapeutic levels and to per mit productive vector readministration have been examined. Our previous stu dies have shown that depletion of macrophages from spleen and liver decreas es hepatic inflammation, significantly prolongs transgene expression, and d elays the onset of humoral immune responses after systemic administration o f an E1-deleted adenovirus vector. In the present study, we have examined t he effects of macrophage depletion in combination with temporary blockade o f CD40 ligation on E1-deleted adenovirus vector-mediated gene transfer. Alo ne, each of these treatments significantly inhibited the humoral immune res ponse against the transgene product and prolonged its expression. Together, these treatments completely stabilized transgene expression and inhibited the production of neutralizing anti-adenovirus antibodies, permitting succe ssful vector readministration. Animals rendered immunologically unresponsiv e to vector and transgene antigens regained their ability to mount producti ve immune responses against the vector after recovery of immune function, b ut remained unresponsive to the transgene product. These experiments demons trate that this treatment is transient and antigen-specific.