CELLULAR AND HUMORAL IMMUNE-RESPONSES TO VIRAL-ANTIGENS CREATE BARRIERS TO LUNG-DIRECTED GENE-THERAPY WITH RECOMBINANT ADENOVIRUSES

Recombinant adenoviruses are an attractive vehicle for gene therapy to the lung in the treatment of cystic fibrosis (CF). First-generation viruses deleted of E1a and E1b transduce genes into airway epithelial cells in vivo; however, expression of the transgene is transient and associated with substantial inflammatory responses, and gene transfer is significantly reduced following a second administration of the virus. In this study, we have used mice deficient in immunological effector Functions in combination with adoptive and passive transfer techniques to define antigen-specific cellular and humoral immune responses that underlie these important limitations, Our studies indicate that major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes are activated in response to newly synthesized antigens, leading to destruction of virus infected cells and loss of transgene expression. Major histocompatibility complex class II-associated presentation of exogenous viral antigens activates CD4(+) T-helper (T-H) cells of the T-H1 subset and, to a lesser extent, of the T-H2 subset, CD4(+) cell-mediated responses are insufficient in the absence of cytotoxic T cells to completely eliminate transgene containing cells; however, they contribute to the formation of neutralizing antibodies in the airway which block subsequent adenovirus-mediated gene transfer. Definition of immunological barriers to gene therapy of cystic fibrosis should facilitate the design of rational strategies to overcome them.