Sepsis is characterised by systemic inflammatory response syndrome (SIRS) following infection which can be caused by a wide variety of pathogens. Suppression of proinflammatory mediators by neutralizing antibodies could be beneficial in the treatment of the disease by targeting the excessive activation of innate immune pathways common to sepsis. Nuclear protein high-mobility group box 1 (HMGB1) has emerged as a key mediator in infection and SIRS, where it acts as an alarmin signalling primarily through RAGE and TLR’s. HMGB1 may also play a role in secondary immunosuppression and nosocomial infection following sepsis which is a significant cause of mortality in septic patients. These contrary roles of HMGB1 have been linked to the redox status of two cysteine residues present on the A-box domain of the circulating protein.
We have demonstrated prolonged HMGB1 release in a cohort of septic patients and found HMGB1 levels to be significantly higher in non-surviving patients. Using TGA- and FDA-approved methodology, we have created potent HMGB1-neutralising ovine polyclonal antibody. Our in vivo experiments revealed anti-HMGB1 administration conferred a survival advantage in a murine endotoxin model, and can significantly reduce morbidity and circulating proinflammatory cytokines in a caecal ligation and puncture peritonitis model.
Our further experiments will work to demonstrate the effect of HMGB1 neutralisation in secondary immunosuppression following sepsis and profile the redox status of circulating HMGB1 in murine sepsis and septic patient plasma.
Together these works will establish the validity of targeting HMGB1 in sepsis and secondary immunosuppression.