IMMEDIATE INFLAMMATORY RESPONSES TO ADENOVIRUS-MEDIATED GENE-TRANSFERIN RAT SALIVARY-GLANDS

Although replication-deficient adenoviruses can efficiently transfer g enes to the salivary glands, the current vectors precipitate an immedi ate, transient decrease in salivary function. To study the cause of th is salivary hypofunction, 10(6)-10(10) plaque-forming units (pfu) of t he vector AdCMV beta gal were delivered by retrograde ductal infusion to the submandibular glands (SMGs) of rats. Microscopic analysis of in fected glands showed a dose-related, rapidly developing inflammatory r esponse, which at the highest amount of virus was characterized by a p redominantly neutrophil-containing infiltrate, focal necrosis, and ede ma. Moreover, the glands of nude rats developed similar morphologic ch anges to those of immunocompetent rats. After 3 days, the volume of st imulated saliva secreted from SMGs receiving AdCMV beta gal (6.75 x 10 (9) pfu) was similar to 20% that of controls. UV-inactivated virus cau sed a similar decrease in saliva output. We evaluated to what extent t he anti-inflammatory glucocorticoid, dexamethasone, could suppress inf lammation and preserve salivary function. Three days after infusion wi th a high dose of AdCMV beta gal (6.75 x 10(9) pfu), the glands from d examethasone-treated animals showed markedly less inflammation and no necrosis. Furthermore, there was no significant difference in the aver age amount of saliva secreted from the infected glands (105 +/- 17 mu l) compared to the control glands (123 +/- 18 Ed). In addition, dexame thasone extended the expression of beta-galactosidase in the SMGs. The se results suggest that the adenovirus-mediated acute inflammation in rat SMG is responsible for diminished gland function and transgene exp ression. Furthermore, we demonstrate a useful role for glucocorticoids in controlling acute inflammation during experimental gene transfer w ith current adenovirus vectors.