Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells.
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.
Oberholzer
Andreas
A
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Oberholzer
Caroline
C
Bahjat
Keith S
KS
Ungaro
Ricardo
R
Tannahill
Cynthia L
CL
Murday
Michelle
M
Bahjat
Frances R
FR
Abouhamze
Zaher
Z
Tsai
Van
V
LaFace
Drake
D
Hutchins
Beth
B
Moldawer
Lyle L
LL
Clare-Salzler
Michael J
MJ
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
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