Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression

Abstract

Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNF-α-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-α-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (10 5 particles) protects, while high-dose adenovirus (10 10 particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF-α dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNF-α appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-α responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.

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

“…These results confirmed our earlier findings in healthy mice that adenoviral expression of viral IL-10 was associated with prolonged and more specific local expression compared to human IL-10. 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.…”

“…We have also reported that intravenous administration of adenovirus exacerbates apoptotic liver injury to a subsequent challenge with D-galactosamine and lipopolysaccharide. 7 In contrast to systemic administration, local delivery of adenovirus has been well tolerated. In fact, adenovirus recombinants are currently in clinical trials as a means to ectopically express growth factors and cytokines for targeted treatment of cancer, rheumatoid arthritis, and chronic wounds.…”

Enhancing the therapeutic efficacy of adenovirus in combination with biomaterials

“…In company with innate immune response, the induction of adaptive immune response has also been reported to be another important obstacle-step to reduce the Ad-delivery efficiency. Although Ad vectors evade all innate/adaptive immune system, almost all of them accumulate in liver followed by acute liver toxicity and leftover Ads locate to anywhere in the body (39). Passively accumulated Ads within solid tumor have a possibility to infect to cancer cells as a result of the poor lymphatic drainage leading to retention of macromolecules within the tumor stroma as well as the leaky vasculature giving high levels of fluid extravasation (40).…”

Efficient Attenuation of NK Cell–Mediated Liver Injury through Genetically Manipulating Multiple Immunogenes by Using a Liver-Directed Vector

“…2E). Simultaneous huIL-10 overexpression and FKN knockdown enhance the attenuating effect of knocking down FKN alone in adenovirus-induced acute liver injury IL-10 functions as a critical regulator of NK cell-related inflammation (11,25,26). We tried to determine whether overexpression of huIL-10 would further enhance the attenuating effect of silencing FKN in adenovirus-induced acute liver injury.…”

“…Knockdown of chemokines such as fractalkine (FKN) to inhibit NK cell recruitment and activity could protect the acute liver injury induced by adenoviral vector (9). Inflammatory cytokines such as IFN and TNF had important roles in adenovirusinduced acute liver injury; therefore, overexpression of inhibitory cytokines IL-10 has also been used to modulate the injury (10,11). Finally, to achieve liver specificity in gene therapy, liver-specific promoters cannot only achieve prolonged transgene expression but also reduce side effects caused by transgene expression in non-liver cells (12,13).…”