Publication

Rapid functional exhaustion and deletion of CTL following immunization with recombinant adenovirus

Journal Paper/Review - Apr 15, 2005

Units
PubMed

Citation
Krebs P, Scandella E, Odermatt B, Ludewig B. Rapid functional exhaustion and deletion of CTL following immunization with recombinant adenovirus. Journal of immunology (Baltimore, Md. : 1950) 2005; 174:4559-66.
Type
Journal Paper/Review (English)
Journal
Journal of immunology (Baltimore, Md. : 1950) 2005; 174
Publication Date
Apr 15, 2005
Issn Print
0022-1767
Pages
4559-66
Brief description/objective

Replication-deficient adenoviruses (recombinant adenovirus (rec-AdV)) expressing different transgenes are widely used vectors for gene therapy and vaccination. In this study, we describe the tolerization of transgene-specific CTL following administration of beta-galactosidase (beta gal)-recombinant adenovirus (Ad-LacZ). Using MHC class I tetramers to track beta gal-specific CTL, we found that a significant expansion of beta gal-specific CTL was restricted to a very narrow dose range. Functional analysis revealed that adenovirus-induced beta gal-specific CTL produced only very low amounts of effector cytokines and were unable to exhibit cytolytic activity in a 51Cr release assay. Furthermore, Ad-LacZ vaccination failed to efficiently clear established beta gal-positive tumors. The impaired function of Ad-LacZ-induced CTL correlated with the presence of persisting beta gal Ag in the liver. A further increase in the peripheral Ag load by injection of Ad-LacZ into SM-LacZ transgenic mice which express beta gal as self-Ag exclusively in peripheral nonlymphoid organs, resulted in the physical deletion of beta gal-specific CTL. Our results indicate first that CTL deletion in the course of adenoviral vaccination is preceded by their functional impairment and second, that the outcome of rec-AdV vaccination depends critically on the Ag load in peripheral tissues.