Anti-high mobility group box-1 monoclonal antibody treatment provides protection against influenza A virus (H1N1)-induced pneumonia in mice

Abstract

IntroductionProvision for the emergence of an influenza pandemic is an urgent issue. The discovery of a novel anti-influenza therapeutic approach would increase the effectiveness of traditional virus-based strategies. This study was undertaken to evaluate the therapeutic effects of anti-high mobility group box-1 (HMGB1) monoclonal antibody (mAb) treatment on influenza A virus (H1N1)-induced pneumonia in mice.MethodsNine-week-old male C57BL/6 mice were inoculated with H1N1, then anti-HMGB1 mAb or control mAb were administered intravenously at 1, 24 and 48 hours after H1N1 inoculation and the survival rate was analyzed. Lung lavage and histopathological analysis were performed on days 3, 5, 7 and 10 after inoculation.ResultsAnti-HMGB1 mAb significantly improved the survival rate of H1N1-inoculated mice (1 out of 15 versus 8 out of 15 deaths in the anti-HMGB1 mAb-treated group versus the control mAb-treated group, p < 0.01), although the treatment did not affect virus propagation in the lungs. The treatment also significantly attenuated histological changes and neutrophil infiltration in the lungs of H1N1-inoculated mice. This was associated with inhibition of HMGB1 and suppression of inflammatory cytokine/chemokine expression and oxidative stress enhancement, which were observed in H1N1-inoculated mice. The expression of receptor for advanced glycation end products and nuclear factor κB was attenuated by the treatment.ConclusionsAnti-HMGB1 mAb may provide a novel and effective pharmacological strategy for severe influenza virus infection in humans by reducing the inflammatory responses induced by HMGB1.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0983-9) contains supplementary material, which is available to authorized users.

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

“…Interestingly, several of the viruses and bacteria that have been implicated in the pathogenesis of asthma are also known to induce HMGB1 (Moisy et al, 2012; Hou et al, 2014; Wang et al, 2004, 1999). Indeed, our preliminary data suggest that later life exposure to either influenza A virus or lipopolysaccharide (known HMGB1 stimuli) (Nosaka et al, 2015; Gardella et al, 2002) are able to induce at least some features of airway remodelling in RAGE deficient mice that were infected with PVM in early life (data not shown). These data thus also raise the possibility that the mechanisms of disease shown here may not be limited to PVM-induced asthma.…”

DAMPs and influenza virus infection in ageing

“…In addition, elevated levels of HMGB-1 and other inflammatory molecules such as IL-6 and RANTES were found in sera from patients with severe bacterial pneumonia co-infected with influenza virus (Kosai et al, 2008). Importantly, treatment of mice with a antibody against HMGB1 results in protection against severe pneumonia in mice infected with H1N1 influenza virus (Nosaka et al, 2015). As HMGB1 is increased during aging, this can predict that influenza virus pathogenesis would be enhanced in elderly patients.…”

Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

“…In contrast, BXSB mice exhibit TLR pathway abnormalities; therefore, the former study could demonstrate favorable results despite the lower treatment dose than the other protocol. Our treatment protocol was determined based on previous studies 19, 20, 21. Moreover, we first tried subcutaneous injection using the same dosage (5 mg/kg) as a preliminary experiment; however, we were not able to find any beneficial effects for MRL/ lpr mice ( data not shown ).…”

“…To elucidate this discrepancy, we examined the efficacy of anti-HMGB1 mAb to determine whether it ameliorates lupus activities, including nephritis and serological abnormalities, in MRL/ lpr lupus-prone mice. Our mAb recognizes the C-terminal sequence of the HMGB1 molecule and can neutralize the intercellular adhesion molecule 1 (ICAM1)-inducing activity of HMGB1 in vitro; 19 moreover, therapeutic effects against brain stroke, atherosclerosis, and viral infections have also been reported 19, 20, 21…”