TNF alpha and IFN gamma induced by innate anti-adenoviral immune responsesinhibit adenovirus-mediated transgene expression

The transient nature of adenovirus-mediated transgene expression has been a ttributed to adaptive immune responses to adenoviral proteins and transgene products. However, the cytokines interferon-gamma (IFN gamma) and tumor ne crosis factor-alpha (TNF alpha) inhibit transgene expression from adenovira l vectors in vitro by a transcription-related mechanism, and their early in duction following vector administration in vivo suggests a contribution of innate immunity in regulating transgene expression. In this study, the sign ificance of cytokine expression and its relation to adaptive and innate imm unities were determined in TNF alpha -knockout mice, IFN gamma -knockout mi ce, or anti-IFN gamma mAb-injected animals. Adenoviral LacZ reporter expres sion directed by human cytomegalovirus (HCMV) promoters was greater in magn itude and duration than that by the murine CMV (MCMV) promoter. beta -Galac tosidase reporter gene expression up to day 7 was greater in cytokine-defic ient animals compared with wild type. Decrements in transgene expression oc curred in advance of adaptive immune responses and were not due to alterati ons in specific adaptive immunity or vector clearance in cytokine-depleted mice. We conclude that TNF alpha and IFN gamma inhibit early adenovirus-med iated transgene expression by HCMV and MCMV promoters in vivo. Cytokine inh ibition of expression is independent of adaptive immunity and is likely sec ondary to innate immune responses to adenovirus infection.