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 (TH) cells of the TH1 subset and, to a lesser extent, of the TH2 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.
Yang
Y
Y
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia 19104.
Li
Q
Q
Ertl
H C
HC
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D000956:Antigens, Viral / Q000276:immunology*; D003550:Cystic Fibrosis / Q000235:genetics / Q000628:therapy*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007111:Immunity, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009500:Neutralization Tests; D011014:Pneumonia / Q000276:immunology / Q000628:therapy; D011995:Recombination, Genetic; D016176:T-Lymphocyte Subsets; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000914:Antibodies, Viral; D000956:Antigens, Viral; D015395:Histocompatibility Antigens Class I