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Production1
Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717
The proposed usage of replication-deficient adenovirus (Ad) vectors
for corrective gene therapy or for mucosal immunization has been
limited in part by the host reactivity to the Ad vector, thus limiting
repeated Ad instillations. We have recently shown that the reactivity
to the Ad vector is in large part due to increased
CD4+ Th1 and Th2 responses as well as elevated IgG
and mucosal IgA responses. It has been recently proposed that the
diminution of transgene expression in respiratory epithelia was due to
increased CTL reactivity to expressed Ad proteins. Herein, we report
that repeated intratracheal delivery of a second generation Ad2 vector
into mice results in no detectable CTL activity in freshly isolated
lymphoid cells from lungs, lower respiratory lymph nodes, or spleens or
after in vitro restimulation. In contrast, a single dose of Ad2 vector
did elicit a robust CTL response. This attenuation of CTL activity was
long lived and was not affected by macrophage depletion or due to a
reduction in CD4+ or CD8+ T cells. Examination
of cytokine production via MHC class I or class II restimulation by
lymphoid cells from three intratracheally treated mice showed an
attenuation in the production of IFN-
by as much as 110-fold. This
reduction in IFN- could not be attributed to increased IL-4 or IL-10
production. Thus, this study shows that the CTL response to Ad vectors
is attenuated upon repeated administration.
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