Use of DAF-displaying adenovirus vectors reduces induction of transgene- and vector-specific adaptive immune responses in mice

• Published in: Human gene therapy Vol. 22; no. 9; p. 1083
• Main Authors: Seregin, Sergey S, Aldhamen, Yasser A, Appledorn, Daniel M, Zehnder, Jennifer, Voss, Tyler, Godbehere, Sarah, Amalfitano, Andrea
• Format: Journal Article
• Language: English
• Published: United States 01.09.2011
• Subjects: Adaptive Immunity; Adenoviridae - genetics; Adenoviridae - immunology; Animals; CD55 Antigens - genetics; Epitopes - immunology; Gene Transfer Techniques; Genetic Vectors - administration & dosage; Genetic Vectors - immunology; HEK293 Cells; Humans; Immunity, Cellular; Immunity, Humoral; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Transduction, Genetic; Transgenes
• ISSN: 1557-7422
• DOI: 10.1089/hum.2010.218

Adenovirus (Ad)-based vectors are attractive candidates for a variety of gene-transfer applications. In this study, we found that decay-accelerating factor (DAF)-displaying Ads induce significantly decreased cellular immune responses to transgenes expressed from the vectors in both Ad5-naive and Ad5-immune mice. Specifically, we found a diminished ability of splenocytes to secrete interferon-γ after recall exposure to multiple peptides derived from antigens expressed by DAF-displaying Ads. We also confirmed that DAF-displaying Ads induce decreased numbers of antigen-specific, CD8(+) effector memory and central memory CD8(+) T cells, thereby uncovering a unique role of complement in modulating the induction of robust memory T-cell responses. We also confirmed that DAF-displaying Ads generate significantly reduced titers of Ad capsid-specific neutralizing antibodies after gene transfer in vivo. In conclusion, DAF-displaying Ad5-based vectors exhibit decreased induction of complement-dependent, innate immune responses, resulting in both an improved safety profile and a decreased propensity to induce humoral and cellular adaptive immune responses to Ad capsid proteins and Ad vector-expressed transgene products. This attractive combination of features will be beneficial in a variety of clinically relevant gene-transfer applications.