title: TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung.
abstract: Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Minter
authors.forename: J E
authors.initials: JE
authors.lastname: Rectenwald
authors.forename: K
authors.initials: K
authors.lastname: Fukuzuka
authors.forename: C L
authors.initials: CL
authors.lastname: Tannahill
authors.forename: D
authors.initials: D
authors.lastname: La Face
authors.forename: V
authors.initials: V
authors.lastname: Tsai
authors.forename: I
authors.initials: I
authors.lastname: Ahmed
authors.forename: E
authors.initials: E
authors.lastname: Hutchins
authors.forename: R
authors.initials: R
authors.lastname: Moyer
authors.forename: E M
authors.initials: EM
authors.lastname: Copeland
authors.forename: L L
authors.initials: LL
authors.lastname: Moldawer
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics*; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology* / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000914:Antibodies, Viral; D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D001616:beta-Galactosidase