Mechanisms of induction of paralysed dendritic cells with poor antigen presentation function following systemic inflammatory response syndrome (APP3P.103)

Abstract

Abstract Severe infections, trauma, burns or hemorrhage trigger SIRS, which is characterized by the release of immune-activating cytokines but is followed by weeks-long immunosuppression. Opportunistic infections post-SIRS are the main cause of mortality and morbidity in critical care patients. Immunosuppression post-SIRS may also contribute to poor vaccination outcomes in areas with high incidence of infection with malaria or other pathogens. We are characterizing the contribution of Dendritic Cell (DC) functional impairment (paralysis) to immunosuppresion in mice where SIRS is triggered by TLR ligands or by infection with viruses, bacteria or the malaria parasite. We show that SIRS changes the local environment where DC undergo final differentiation, leading to weeks-long formation of paralyzed DC with poor antigen presentation function. We have (i) characterized the mechanisms responsible for this defect; (ii) identified a unique genetic program induced in paralyzed DC; (iii) devised strategies to overcome the impaired antigen presenting function of paralyzed DC; (iv) discovered cytokines that induce local formation of paralyzed DC; and (v) blocked these cytokines with mAb to reduce paralysis. Our studies might lead to new therapies to overcome DC paralysis and restore immunocompetence post-SIRS, preventing secondary infections and death in intensive care patients. They may also lead to improved vaccination outcomes in areas with high incidence of pathogen infection.