Pharmacokinetic differences between a T cell-tolerizing and a T cell-activating peptide

Vaccination with a peptide representing a CTL epitope from the human papill omavirus (HPV)16 E7 protein induces a specific CTL response that prevents t he outgrowth of HPV16 E7-expressing tumors. In contrast, vaccination with a peptide encoding an adenovirus type 5 (Ad5) E1A CTL epitope results in CTL tolerance and enhanced growth of an Ad5 EIA-expressing tumor. It is unclea r why these peptides induce such opposite effects. To determine whether a d ifference in pharmacokinetics can explain the functional contrasts, tritiat ed Ad5 E1A and HPV16 E7 peptides were injected into mice. Results show that the tolerizing peptide spread through the body 16 times faster than the ac tivating peptide and was cleared at least 2 times faster. The HPV16 E7 pept ide kinetics correlated with the kinetics of HPV16 E7-specific CTL inductio n. In contrast, Ad5 E1A peptide injection resulted in physical deletion of preexisting Ad5 E1A-specific CTLs within 24 h after injection. This toleriz ation occurred at the time when the peptide reached its maximum peptide con centration in the organs. These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activat ion-induced cell death of Ad5 EIA-specific CTLs. Therefore, information on the pharmacokinetics of peptides is vital for the safety and efficacy of pe ptide-based vaccines.