Dw. Pascual et al., REPEATED INTRATRACHEAL INSTILLATIONS OF NONREPLICATING ADENOVIRUS-2 VECTOR ATTENUATE CTL RESPONSES AND IFN-GAMMA PRODUCTION, The Journal of immunology, 160(9), 1998, pp. 4465-4472
The proposed usage of replication-deficient adenovirus (Ad) vectors fo
r corrective gene therapy or for mucosal immunization has been limited
in part by the host reactivity to the Ad vector, thus limiting repeat
ed Ad instillations. We have recently shown that the reactivity to the
Ad vector is in large part due to increased CD4(+) Th1 and Th2 respon
ses as well as elevated IgG and mucosal IgA responses. It has been rec
ently proposed that the diminution of transgene expression in respirat
ory epithelia was due to increased CTL reactivity to expressed Ad prot
eins. Herein, we report that repeated intratracheal delivery of a seco
nd generation Ad2 vector into mice results in no detectable CTL activi
ty in freshly isolated lymphoid cells from lungs, lower respiratory ly
mph nodes, or spleens or after in vitro restimulation, In contrast, a
single dose of Ad2 vector did elicit a robust CTL response. This atten
uation of CTL activity was long lived and was not affected by macropha
ge depletion or due to a reduction in CD4(+) or CD8(+) T cells. Examin
ation of cytokine production via MRC class I or class II restimulation
by lymphoid cells from three intratracheally treated mice showed an a
ttenuation in the production of IFN-gamma by as much as 110-fold, This
reduction in IFN-gamma could not be attributed to increased IL-4 or I
L-10 production. Thus, this study shows that the CTL response to Ad ve
ctors is attenuated upon repeated administration.