REPETITIVE ADENOVIRUS ADMINISTRATION TO THE PAROTID-GLAND - ROLE OF IMMUNOLOGICAL BARRIERS AND INDUCTION OF ORAL TOLERANCE

This study assessed the mucosal and systemic immune responses followin g repetitive adenoviral vector instillation to the parotid glands, Als o, we investigated the feasibility of oral tolerance induction as a ra tional strategy to overcome the immunological reactions, The replicati on-deficient recombinant adenovirus vector AdCMVCAT was instilled into rat parotid glands, Chloramphenicol acetyltransferase (CAT) activity in the parotid was observed after a first or second AdCMVCAT infection , but not after a third vector administration, ELISA assays showed inc reased anti-adenovirus immunoglobulin G (IgG) and IgM in serum, and al so anti-adenovirus IgA in gland extracts and saliva after virus admini stration, The results of in vivo neutralization experiments demonstrat ed that salivary IgA and IgM prevented reinfection of the parotids wit h adenoviral vectors, Subsequently, studies were conducted to induce t olerance to adenovirus by peroral feedings of ultraviolet (UV)-inactiv ated virus before gene administration to the parotid glands, Between 3 and 13 doses of virus were fed to rats, Final parotid gene expression was dependent on the number of viral feedings and the amount fed, Tol erized animals showed prolonged and heightened gene expression in the salivary glands compared to control animals and displayed gene express ion even after three administrations of vector, Mononuclear cells from the spleens of these animals showed reduced proliferation following a denovirus stimulation, This same cell population was depleted of CD8() T cells and found to produce less interferon-gamma (IFN-gamma) after virus challenge, This profile indicates the down regulation of Th1 ce ll-mediated responses, These results indicate that oral tolerance indu ction is a potentially useful adjunct to virus-based gene therapy.