GENERATION OF AN EFFECTIVE IN VIVO CTL RESPONSE USINGVACCINE APPROACHES IN A MODEL OF AUTOIMMUNITY

Abstract

Background: Various interactions between tumours and their environment make it difficult to determine the factors that are essential to the induction of a robust CTL response by immunotherapeutic strategies against tissue antigens. We therefore sought to develop a model of autoimmunity, in which vaccine strategies could be evaluated for their ability to elicit CTL activity towards a model antigen. Methods: Transgenic mice expressing lymphocytic choriomeningitis virus glycoprotein (LCMV-gp) specifically in the insulin-producing beta-islets of the pancreas allowed anti-beta islet CTL responses to be measured by blood glucose levels, tetramer and intracellular cytokine staining. Peptide vaccines consisted of i.v. administration of the known immunodominant epitopesof LCMV-gp alongside dendritic cell (DC) maturation stimuli. DC vaccines consisted of i.v.administration of 2x10^6 mature LCMV-gp peptide-pulsed bone-marrow-derived DC. Results: While administration of antigenic peptides with adjuvants and/or costimulatory molecules were ineffective, DC vaccination induced hyperglycemia in approximately 70% of mice. Interestingly, while a class II epitope was not required for induction of autoimmunity, pulsing with a single class I epitope was insufficient. Furthermore, while tetramer-positive populations could be seen in the blood of peptide-vaccinated mice, no such population is seen in DC-treated mice. Conclusions: The lack of correlation between presence of tetramer-positive populations in the blood and effective beta-islet cell cytolysis underlines the requirement for better markers of CTL activity inclinical trials. These results demonstrate the effectiveness of DC vaccination in this model and allow for further investigation of the factors that direct a strong CD8+ T-cell response towards tissue antigens.