Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naïve and pre-immunized mice

• Published in: Gene therapy Vol. 12; no. 5; pp. 427 - 436
• Main Authors: VARNAVSKI, A. N, CALCEDO, R, BOVE, M, GAO, G, WILSON, J. M
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-03-2005
• Subjects: Adaptive immunity; Adenoviridae - genetics; Adenoviridae Infections - immunology; Adenoviridae Infections - mortality; Adenovirus; Adenoviruses; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; Bone growth; Bone marrow; Bone Marrow - virology; Cytokines; Cytokines - immunology; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic aspects; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic vectors; Genetic Vectors - toxicity; Health. Pharmaceutical industry; Humans; Immune response; Immunity; Immunization; Immunoglobulin G - blood; Industrial applications and implications. Economical aspects; Inflammation; Leukopenia; Leukopenia - etiology; Liver - enzymology; Liver - virology; Macaca mulatta; Medical sciences; Mice; Mice, Inbred C57BL; Physiological aspects; Serotypes; Thrombocytopenia; Thrombocytopenia - etiology; Toxicity; Transaminases - blood; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; United States; Adenoviridae; Intravenous administration; Toxicity; Rodentia; Virus; Vertebrata; Mammalia; Mouse; innate immunity; adenovirus; Gene therapy; High dose; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302347

Toxicity associated with in vivo administration of adenovirus (Ad) vectors has been linked to activation of both innate and adaptive immune responses. Pre-existing immunity to the prevalent Ad serotypes, acquired by the majority of the human population as a result of natural infections, has the potential to modulate vector efficacy and safety. Previously, we evaluated some aspects of toxicity from systemic Ad vector in vector-naive and pre-immunized rhesus monkeys. In this report, we summarize data from several studies analyzing toxic effects from systemically administered E1/E3-deleted Ad vector in vector-naive and pre-immunized C57BL/6 mice. Our results indicate that pre-immunization can be associated with increased mortality shortly after systemic administration of Ad. Transient leukopenia and thrombocytopenia were observed early post vector infusion in both vector-naive and pre-immunized animals. Pre-exposure to the vector did not prevent induction of pro-inflammatory cytokines; however, pre-immunized mice showed less tissue toxicity. Growth of bone marrow myeloid and erythroid progenitors was transiently inhibited in pre-immunized animals, but only the myeloid progenitors were affected in vector-naive animals. In summary, pre-existing immunity to Ad vector substantially modifies host immune responses to systemic Ad vector.