Adenoviral vector-mediated gene therapy in the mouse lung: no role of Fas-Fas ligand interactions for elimination of transgene expression in bronchioepithelial cells.
The early successes of adenoviral vector-mediated gene therapies in the lung have been hampered by the immune response directed against viral proteins and transgene product. Intratracheal administration of adenovirus vector in immune-competent mice transduces bronchioepithelial cells of lung extremely efficiently; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs). Fas-Fas ligand (Fas-FasL) interactions play a critical role in the effector function of the CTL killing. We have previously demonstrated that this interacting pair of molecules plays a critical role in elimination of transgene expression in mouse liver. In this study we investigated the role of Fas-FasL interactions in CTL effector functions in vivo in mouse lung. Analyses of these molecules in lung showed constitutive expression of Fas in bronchiooepithelial cells. On the other hand, FasL was inducible in the bronchioepithelial cells after adenovirus vector treatment. The in vivo role of the Fas-FasL interactions was determined by adoptive transfer of splenocytes from normal immune-competent mice to Fas-deficient mice (B6-lpr); likewise, the function of FasL on CTLs was analyzed by the ability of splenocytes from FasL-deficient mice (B6-gld) to eliminate transgene expression in Rag1-deficient mice. These studies demonstrate that despite expression of Fas and FasL in bronchioepithelial cells and CTLs, these interacting molecules do not play a critical role in elimination of transgene expression in the lung.
Chirmule
N
N
Department of Molecular and Cellular Engineering and Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia 19104, USA. chirmule@mail.med.upenn.edu
Moffett
J
J
Dhagat
P
P
Tazelaar
J
J
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D053222:Fas Ligand Protein; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019076:Transgenes; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor