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Gene Ther. 2005 Mar;12(5):427-36.

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

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1
Gene Therapy Program at the University of Pennsylvania School of Medicine, Department of Medicine, Division of Medical Genetics, Philadelphia, PA, USA.

Abstract

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.

PMID:
15647774
DOI:
10.1038/sj.gt.3302347
[Indexed for MEDLINE]
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