Document Detail

Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice.
MedLine Citation:
PMID:  15647774     Owner:  NLM     Status:  MEDLINE    
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.
A N Varnavski; R Calcedo; M Bove; G Gao; J M Wilson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Gene therapy     Volume:  12     ISSN:  0969-7128     ISO Abbreviation:  Gene Ther.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-23     Completed Date:  2005-05-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9421525     Medline TA:  Gene Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  427-36     Citation Subset:  IM    
Gene Therapy Program at the University of Pennsylvania School of Medicine, Department of Medicine, Division of Medical Genetics, Philadelphia, PA, USA.
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MeSH Terms
Adenoviridae / genetics*
Adenoviridae Infections / immunology*,  mortality
Bone Marrow / virology
Cytokines / immunology
Gene Therapy / adverse effects*,  methods
Genetic Vectors / toxicity*
Immunoglobulin G / blood
Leukopenia / etiology
Liver / enzymology,  virology
Mice, Inbred C57BL
Thrombocytopenia / etiology
Transaminases / blood
Grant Support
P01 HL59407-03/HL/NHLBI NIH HHS; P30 DK47757-09/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Cytokines; 0/Immunoglobulin G; EC 2.6.1.-/Transaminases

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