REPEATED INTRATRACHEAL INSTILLATIONS OF NONREPLICATING ADENOVIRUS-2 VECTOR ATTENUATE CTL RESPONSES AND IFN-GAMMA PRODUCTION

Citation
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
Citations number
39
Categorie Soggetti
Immunology
Journal title
ISSN journal
00221767
Volume
160
Issue
9
Year of publication
1998
Pages
4465 - 4472
Database
ISI
SICI code
0022-1767(1998)160:9<4465:RIIONA>2.0.ZU;2-S
Abstract
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.