Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo
Open Access
- 1 June 2004
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 78 (11) , 5966-5972
- https://doi.org/10.1128/jvi.78.11.5966-5972.2004
Abstract
Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted 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 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding 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 posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. 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 levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.Keywords
This publication has 44 references indexed in Scilit:
- Acute Toxicity After High-Dose Systemic Injection of Helper-Dependent Adenoviral Vectors into Nonhuman PrimatesHuman Gene Therapy, 2004
- The role of selectins and integrins in adenovirus vector-induced neutrophil recruitment to the liverEuropean Journal of Immunology, 2002
- Effect of Promoters and Enhancers on Expression, Transgene DNA Persistence, and Hepatotoxicity After Adenoviral Gene Transfer of Human Apolipoprotein A-IHuman Gene Therapy, 2002
- Adenovirus Vector-Induced Inflammation: Capsid-Dependent Induction of the C-C Chemokine RANTES Requires NF-κBHuman Gene Therapy, 2002
- Acute Direct Adenoviral Vector Cytotoxicity and Chronic, but Not Acute, Inflammatory Responses Correlate with Decreased Vector-Mediated Transgene Expression in the BrainMolecular Therapy, 2001
- Prolonged Transgene Expression Mediated by a Helper-Dependent Adenoviral Vector (hdAd) in the Central Nervous SystemMolecular Therapy, 2000
- Adenoviral Gene Therapy Leads to Rapid Induction of Multiple Chemokines and Acute Neutrophil-Dependent Hepatic Injury in VivoHuman Gene Therapy, 1999
- Cytotoxic T Lymphocyte Responses to Proteins Encoded by Heterologous Transgenes TransferredIn Vivoby Adenoviral VectorsHuman Gene Therapy, 1997
- Innate Immune Mechanisms Dominate Elimination of Adenoviral Vectors FollowingIn VivoAdministrationHuman Gene Therapy, 1997
- Pulmonary Inflammation Induced by Incomplete or Inactivated Adenoviral ParticlesHuman Gene Therapy, 1995