title: Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells.
abstract: The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells. Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses. In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs. Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression. However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node. The extent of IL-10 expression is dose dependent; transduction with low particle numbers (10(5)) yields only local expression, while transduction with higher particle numbers (10(7) and 10(10)) leads additionally to IL-10 appearance in the circulation. Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (10(5)) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response.
authors.affiliation: Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Oberholzer
authors.forename: Caroline
authors.initials: C
authors.lastname: Oberholzer
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ungaro
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Tannahill
authors.forename: Michelle
authors.initials: M
authors.lastname: Murday
authors.forename: Frances R
authors.initials: FR
authors.lastname: Bahjat
authors.forename: Zaher
authors.initials: Z
authors.lastname: Abouhamze
authors.forename: Van
authors.initials: V
authors.lastname: Tsai
authors.forename: Drake
authors.initials: D
authors.lastname: LaFace
authors.forename: Beth
authors.initials: B
authors.lastname: Hutchins
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology*; D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality*; D016019:Survival Analysis; D013950:Thymus Gland / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000093242:Interleukin-6 Inhibitors
chemical_list: D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D016753:Interleukin-10; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse