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Early Adenoviral Gene Expression Mediates Immunosuppression by Transduced Dendritic Cell (DC): Implications for Immunotherapy Using Genetically Modified DC¹

Andrea Tuettenberg^*, Helmut Jonuleit^*, Thomas Tüting^*,, Jürgen Brück^*, Volker Biermann, Stefan Kochanek^,, Jürgen Knop^* and Alexander H. Enk^2,*

^* Department of Dermatology, J. Gutenberg-University, Mainz, Germany; Department of Dermatology, Bonn, Germany; Center for Molecular Medicine, Köln, Germany; and Division of Gene Therapy, University of Ulm, Ulm, Germany

Long-lasting, high-level gene expression in the absence of a toxic or inflammatory response to viral Ags is necessary for the successful application of genetically modified dendritic cell (DC). We previously demonstrated that efficient transduction of mature DC using E1E3 adenoviruses suppressed their stimulatory capacity for T cells. The current study was designed to investigate in more detail the suppressive effect of Ad-DC. We demonstrate that immunosuppression is not mediated by alterations in the T cell phenotype or cytokine profiles released by stimulated T cells. Also DC phenotypes are not affected. However, we demonstrate a cell cycle arrest of the T cell population stimulated by adenovirally transduced DC. Surprisingly, only freshly transduced DC are perturbed in their stimulatory capacity. Experiments using cycloheximide to block early intracellular viral gene expression showed that viral genes expressed in DC are responsible for this transient immunosuppression. In agreement with these findings, high-capacity (gutless) Ad-vectors that differ in viral gene expression from conventional E1E3 adenovirus are suitable for an efficient transduction of human DC. DC transduced with gutless Ad-vectors showed a high allostimulatory capacity for CD4⁺ and CD8⁺ T cells. Thus, the immunosuppressive effect of E1E3 Ad-transduced mature DC seems to be the result of early viral gene expression in DC that can be prevented using gutless Ad-vectors for transduction. These results have important implications for the use of genetically modified DC for therapeutic application.

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