Adenoviral delivery of human and viral IL-10 in murine sepsis.
Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system for the targeted administration of protein-based therapies, including growth factors and biological response modifiers. However, inflammation associated with Ad transduction has raised concern about its safety and efficacy in acute inflammatory diseases. In the present report, intratracheal and i.v. administration of a first-generation adenoviral recombinant (E1,E3 deleted) either containing an empty cassette or expressing the anti-inflammatory cytokines viral or human IL-10 (IL-10) was administered to mice subjected to zymosan-induced multisystem organ failure or to acute necrotizing pancreatitis. Pretreatment of mice with the intratracheal instillation of Ad expressing human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflammatory cytokine response, and reduced mortality in the zymosan-induced model, whereas pretreatment with a control adenoviral recombinant did not significantly exacerbate the response. Pretreatment of mice with pancreatitis using adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered systemically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and expression of the anti-inflammatory protein IL-10 can be used to suppress the underlying inflammatory process.
Minter
R M
RM
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Ferry
M A
MA
Murday
M E
ME
Tannahill
C L
CL
Bahjat
F R
FR
Oberholzer
C
C
Oberholzer
A
A
LaFace
D
D
Hutchins
B
B
Wen
S
S
Shinoda
J
J
Copeland
E M
EM
Moldawer
L L
LL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D002796:Choline Deficiency / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005001:Ethionine / Q000633:toxicity; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000235:genetics*; D007442:Intubation, Intratracheal; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014764:Viral Proteins / Q000008:administration & dosage* / Q000235:genetics*; D015054:Zymosan / Q000633:toxicity
D000963:Antimetabolites; C066460:BCRF1 protein, Human herpesvirus 4; D016207:Cytokines; D014764:Viral Proteins; D016753:Interleukin-10; D015054:Zymosan; D005001:Ethionine