Adenoviral delivery of human and viral IL-10 in murine sepsis

Adenovirus (Ad) gene therapy has been proposed as a drug-delivery system fo r 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 a cute inflammatory diseases. In the present report, intratracheal and Lv. ad ministration of a first-generation adenoviral recombinant (E1,E3 deleted) e ither containing an empty cassette or expressing the anti-inflammatory cyto kines viral or human IL-10 (IL-10) was administered to mice subjected to zy mosan-induced multisystem organ failure or to acute necrotizing pancreatiti s. Pretreatment of mice with the intratracheal instillation of Ad expressin g human IL-10 or viral IL-10 reduced weight loss, attenuated the proinflamm atory cytokine response, and reduced mortality in the zymosan-induced model , whereas pretreatment with a control adenoviral recombinant did not signif icantly exacerbate the response. Pretreatment of mice with pancreatitis usi ng adenoviral vectors expressing IL-10 significantly reduced the degree of pancreatic and liver injury and liver inflammation when administered system ically, but not intratracheally. We conclude that adenoviral vectors can be administered prophylactically in acute inflammatory syndromes, and express ion of the anti-inflammatory protein IL-10 can be used to suppress the unde rlying inflammatory process.