Rapid functional exhaustion and deletion of CTL following immunization with recombinant adenovirus.
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.
Krebs
Philippe
P
Research Department, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
Scandella
Elke
E
Odermatt
Bernhard
B
Ludewig
Burkhard
B
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics; D005260:Female; D005822:Genetic Vectors; D007108:Immune Tolerance; D007114:Immunization; D066298:In Vitro Techniques; D007763:Lac Operon; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology
D019496:Cancer Vaccines; D001616:beta-Galactosidase