HMGB1- An Immunotherapeutic Target for the Treatment of Neonatal Sepsis and Associated Neuroinflammation

Abstract

Neonatal sepsis remains one of the leading causes of death in the neonatal intensive care unit. Preterm infants and infants with very low birthweight are at increased risk of sepsis and its associated morbidities. Whilst developments in supportive care and antimicrobial advancements have decreased mortality within this population, there has been minimal improvement in the long-term consequences of survival. Therefore, there remains a requirement for therapies for this vulnerable population that improve not only mortality rates, but also morbidity outcomes. Immunotherapies targeting innate inflammatory mediators may provide protection from the lethal effects of uncontrolled persistent inflammation as observed in sepsis. In this thesis, ovine polyclonal antibodies were generated against the late inflammatory mediator HMGB1 using proprietary adjuvant CoVaccine HTTM. It was found that these antibodies had potent binding affinity and neutralising capacity in vivo and in vitro. Administration of these antibodies during murine neonatal sepsis conferred significant reductions in mortality and inflammatory profiles in serum, spleen, and brain tissues. Tissues taken from sepsis survivors displayed immunological memory; protective effects of treatment with pAb α-HMGB1 pAb antibodies was observed both shortly after sepsis recovery and within microglia/macrophage cells during adulthood. Evaluation of behavioural deficits in adulthood displayed improved outcomes with pAb α-HMGB1 treatment. In summary these studies, together with a pilot study investigating HMGB1 during human preterm neonatal sepsis, supports therapeutic targeting of HMGB1 within this population to reduce mortality and associated immunological and neurological consequences of neonatal sepsis.