Adenoviral Delivery of Human and Viral IL-10 in Murine Sepsis

Abstract

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.

Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure

“…11,12 In the present report, we confirmed that at a dose of 10 7 , survival after induction of zymosan lung injury with pre-treatment with buffer or various adenoviral vectors at 10 7 particles). As seen previously, 13 the effects of adenoviral recombinants expressing viral IL-10 were markedly better than those seen with human IL-10, although both treatments improved outcome significantly. In animals pretreated with adenovirus expressing viral IL-10, mortality 18 days after zymosan administration was less than 10%, whereas mortality was 50% for animals pretreated with adenovirus expressing human IL-10, and 100% for the vehicle-treated animals.…”

“…[25][26][27] We previously reported that intratracheal instillation of low dose (10 7 p) adenoviral recombinants expressing IL-10 reduced the magnitude of the inflammatory response to zymosan, 13 and similar results were seen here (data not shown). Interestingly, pretreatment with 10 9 particles of human and viral IL-10 was associated with a significant increase in the magnitude of the inflammatory response, as determined by increased plasma concentrations of TNFa and IL-6 ( Figure 3).…”

“…In a previous report, 13 we observed that targeted lung expression of viral or human IL-10 delivered by a firstgeneration adenoviral recombinant could reduce lung injury and inflammation, and improve outcome in a zymosan model of acute lung injury and MSOF. In that report, we demonstrated that intra-tracheal pretreatment with the adenovirus expressing IL-10 was required, whereas intravenous administration of equivalent quantities of adenovirus was ineffective.…”

“…[8][9][10] We have reported that intratracheal instillation of an E1,E3-deleted adenovirus expressing interleukin-10 (IL-10) can generate local production of IL-10 11,12 and can modify outcome in a number of chronic and acute inflammatory processes, including sepsis and acute pancreatitis. 13 Similar results were not seen when the same recombinants were given systemically. In a previous study, we demonstrated improved outcome and reduced lung injury in response to adenoviral expression of IL-10 in a zymosan-induced model of acute lung injury and multisystem organ failure (MSOF).…”

“…In a previous study, we demonstrated improved outcome and reduced lung injury in response to adenoviral expression of IL-10 in a zymosan-induced model of acute lung injury and multisystem organ failure (MSOF). 13 Standiford et al 14,15 have reported similar results using adenovirus with other biological response modifiers in additional models of acute lung injury.…”