Evaluation of toxicity from high-dose systemic administration of recombinant adenovirus vector in vector-naive and pre-immunized mice.
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.
Varnavski
A N
AN
Gene Therapy Program at the University of Pennsylvania School of Medicine, Department of Medicine, Division of Medical Genetics, Philadelphia, PA, USA.
Calcedo
R
R
Bove
M
M
Gao
G
G
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics*; D000257:Adenoviridae Infections / Q000276:immunology* / Q000401:mortality; D000818:Animals; D001853:Bone Marrow / Q000821:virology; D016207:Cytokines / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000633:toxicity*; D006801:Humans; D007109:Immunity; D007074:Immunoglobulin G / Q000097:blood; D007970:Leukopenia / Q000209:etiology; D008099:Liver / Q000201:enzymology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D013921:Thrombocytopenia / Q000209:etiology; D000637:Transaminases / Q000097:blood
D016207:Cytokines; D007074:Immunoglobulin G; D000637:Transaminases