Pa. Fields et al., Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice, GENE THER, 8(5), 2001, pp. 354-361
Inbred immunocompetent C57BL/6 mice have been a favored strain to study tra
nsgene expression of human blood coagulation factor IX (hF.IX) from viral v
ectors because systemic expression of the secreted protein is not limited b
y antibody responses following intravenous (i.v.) injection of vector. For
example, i.v. injection of an adenoviral (Ad) vector results in sustained e
xpression of hF.IX in normal or hemophilic C57BL/6 mice, while anti-hF.IX a
ntibodies rapidly emerge in other strains (Gene Therapy 4: 473; Blood 91: 7
84). To investigate these observations further, we injected naive C57BL/6 m
ice and C57BL/6 mice with pre-existing anti-hF.IX with Ad-hF.IX vector via
peripheral vein. All mice expressed hF.IX antigen without detectable anti-h
F.IX, even when challenged with hF.IX in different immunogenic settings at
later time points. Moreover, in mice with pre-existing immunity, anti-hF.IX
titers diminished to undetectable levels after i.v. administration of Ad-h
F.IX. Lymphocytes from mice that had received Ad-hF.IX i.v. failed to proli
ferate when stimulated with hF.IX in vitro after the animals had been repea
tedly challenged with hF.IX protein formulated in complete Freund's adjuvan
t. Thus, absence of anti-hF.IX in C57BL/6 mice after i.v. injection of Ad v
ector is not due to ignorance to the foreign transgene product. Similar exp
eriments in other strains showed that immune tolerance to hF.IX does not co
rrelate with the strain haplotype or expression of IL-10 cytokine. Given th
e well-documented immunogenicity of the first-generation adenoviral vector,
data from C57BL/6 mice may therefore grossly underestimate immunological c
onsequences in certain gene therapy protocols.