Recombinant IL–12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung

Abstract

Enthusiasm for the use of recombinant adenoviruses in gene therapy has been tempered by the problematic immune responses that develop to the virus and virus–infected cells. Humoral immune responses to the input viral proteins generate neutralizing antibodies that thwart attempts to effectively administer the therapy more than once. Previous studies in murine models of gene therapy for cystic fibrosis (CF) have shown that the formation of adenoviral antibodies of the IgA subtype, a process that is dependent on T helper cells of the T_H2 subset, contributes to a block in gene transfer that occurs following a second administration of virus. We show in this report that coadministration of interferon–γ (IFN–γ) (or interleukin–12, which activates T_H1 cells to secrete IFN–γ) with the recombinant adenovirus into the airway of C57BL/6 mice diminishes the activation of T_H2 cells and formation of neutralizing antibody, allowing for efficient readministration of recombinant virus. This suggests a strategy for gene therapy of CF in which administration of a short–acting immune modulator at the time of gene therapy may be sufficient to overcome the problems of humoral immunity.