TRANSIENT SUBVERSION OF CD40 LIGAND FUNCTION DIMINISHES IMMUNE-RESPONSES TO ADENOVIRUS VECTORS IN MOUSE-LIVER AND LUNG TISSUES

First-generation adenovirus vectors will have limited application in g ene therapy for chronic diseases because of destructive host immune re sponses. Important immune effecters include CD8(+) T cells, which medi ate target cell destruction and ablate transgene expression, and B cel ls, which produce neutralizing antibodies that block effective readmin istration of vector. Previous studies indicated that activation of CD4 (+) T cells by virus capsid proteins is necessary for full realization of effector function of CD8(+) T cells and B cells. In this paper, we present a strategy for preventing CD4 T-cell activation by an adenovi rus vector delivered to mouse liver and lung tissues which is based on interfering with T-cell priming via CD40 ligand-CD40 interactions. Ad enovirus transgene expression was stabilized in mice genetically defic ient in CD40 ligand (CD40L), and neutralizing antibody to adenovirus d id not develop, allowing efficient readministration of vector. A trans ient blockade of T-cell activation with an antibody to CD40L infused i nto the animal at the time of adenovirus vector-mediated gene transfer led to stabilization of transgene expression and diminished productio n of neutralizing antibody, allowing readministration of vector. In vi tro T-cell assays suggested that a block in the primary activation of CD4(+) T cells was responsible for the lack of B-cell- and cytotoxic-T -cell-dependent responses. This suggests a strategy for improving the potential of adenovirus vectors based on administration of an antibody to CD40L at the time of vector administration.