1014. Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo

Abstract

Helper-dependent adenovirus vectors (HD-Ad) deleted all of adenoviral genes mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1-deleted first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad induce innate and adaptive immune responses in vivo, however, a comprehensive analysis of host immune responses to HD-Ad has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad encoding LacZ (HD-AdLacZ) or murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including IP-10, MIP-2 and TNF-α, and were expressed in a pattern similar to that induced by a FG-Ad encoding murine secreted alkaline phosphatase (AdSEAP). Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3 positive lymphocytic infiltrates 7 days post-transduction. In contrast, beyond 24 hours no infiltrates or expression of inflammatory genes were detected in the livers of mice receiving HD-AdSEAP, even when increasing titers were administered. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T-lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since transgene expression and the amount of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad induce intact innate but attenuated adaptive immune responses in vivo.