HUMORAL AND CELLULAR IMMUNE-RESPONSES OF NONHUMAN-PRIMATES TO LONG-TERM REPEATED LUNG EXPOSURE TO AD2 CFTR-2/

To evaluate the host immune response to long-term repeat administratio n of adenovirus vector, rhesus monkeys were treated at intervals of ap proximately 3 weeks with up to 18 instillations of Ad2/CFTR-2, a secon d generation vector encoding the cystic fibrosis transmembrane conduct ance regulator (CFTR). All monkeys instilled with Ad2/CFTR-2 developed a significant humoral immune response against adenovirus but not CFTR . Antibodies with virus neutralizing activity were detected in the ser um and bronchoalveolar lavage (BAL) of all vector-treated monkeys and included both IgG and secretory IgA. Virus-specific T cells capable of proliferating in response to stimulation with adenovirus antigen were detected in all vector-treated monkeys. No CFTR-specific proliferatio n of peripheral blood lymphocytes was detected. An increase in the pro portion of CD8(+) T cells was noted in the BAL of virus-treated monkey s but cells from the BAL displayed little or no cytolytic activity aga inst infected autologous fibroblasts when tested under a variety of cu lture conditions. However, MHC-restricted cytolytic activity was detec ted in the tracheobronchial lymph nodes and spleen of one of three vir us-treated monkeys tested. MHC-unrestricted killing of infected fibrob lasts was also observed with spleen cells from all animals tested. Fro m these results, it appears that both the humoral and cell-mediated ar ms of the immune response were stimulated by repeated administration o f high doses of Ad2/CFTR-2 suggesting that effective, long-term adenov irus gene therapy may require modification of the vector or treatment of the host to allow the virus to evade host immune defenses.