Evaluation of cellular immune responses in rhesus monkeys subjected to adenovirus-mediated gene transfer into the cervix.

Abstract

We reported previously that direct injection of a recombinant adenovirus (rAd), Ad5CMV-beta-gal, into the cervix of the rhesus monkey resulted in efficient beta-galactosidase expression in the cervix within 3 days. In these studies, we also observed the induction of anti-adenovirus (Ad)-specific immunoglobulin G responses after 22 days. In the continuation of evaluating the anti-Ad-specific immune responses resulting from this approach of gene targeting to the cervix, we measured the cellular immune responses. The introduction of Ad5CMV-beta-gal into the cervix by direct injection, but not by the abrasion technique, resulted in the induction of strong proliferative responses against extracts of cells infected with Ad5CMV-beta-gal but not against control uninfected cells. These responses were initially detected at 22 days postinjection and coincided with the abrogation of transgene expression. Significant levels of proliferative responses were maintained for < or =83 days. Multiple injections of rAds had no significant enhancing effect on either the level or longevity of the proliferative responses. At 3 days after the injection of Ad5CMV-beta-gal, when the transgene expression in the cervix was clearly evident, proliferative responses against the rAd were not detectable. However, the production of low but significant amounts of interleukin-10, a cytokine characteristic of T helper type 2 responses that promote humoral immune responses, was observed at the 3-day point in these animals. These results suggest that significant differences exist between the kinetics of transgene expression and the priming of specific host immune responses, and that these differences may be important for devising alternate strategies to improve techniques for Ad-mediated gene therapy of cervical cancer.