Our lab is studying several aspects of sepsis and the systemic inflammatory response syndrome. A major interest is to define mechanisms of sepsis-induced systemic inflammation and organ injury with emphasis on the roles of natural killer (NK) and T lymphocytes. Current studies are being performed to evaluate the mechanisms of NK and T cell activation and chemotaxis during sepsis with emphasis on the chemokine receptor CXCR3 and its ligands, CXCL9 and CXCL10. The Sherwood group showed that CXCR3 activation is crucial for NK cell trafficking during sepsis and that CXCR3 blockade will decrease inflammation and organ injury in experimental models of sepsis. The underlying goal is to further understand the contribution of CXCR3 activation in the pathogenesis of sepsis and develop clinically relevant interventions to block CXCR3 and improve outcome.
In further studies, Dr. Sherwood’s lab group is evaluating the immunomodulatory properties of TLR4 agonists and their ability to modify the host response to systemic infection. The group showed that the TLR4 agonists lipopolysaccharide and monophosphoryl lipid A are potent immunomodulators that alter systemic cytokine production and enhance innate resistance to bacterial infections. The improved resistance to infection is caused by neutrophil expansion and enhanced neutrophil functions. The group is working to define the mechanisms by which TLR4 agonists promote the antimicrobial functions of neutrophils and develop TLR4 agonists as agents that can be used clinically to improve the resistance of critically ill patients to infection.
Additionally, our lab is focused on the immunological effects of IL-15 superagonist (IL-15 SA). IL-15 SA is complex composed of IL-15 and its receptor α and currently considered as a new promising candidate for cancer immunotherapy by increasing immunological effects of IL-15. Despite of its potent anti-tumor effect, we found systemic administration of IL-15 SA leads to severe toxicity in mice. Our studies indicates that natural killer cells appear to be the primary cell type mediating IL-15 SA-induced immunotoxicity. The underlying molecular mechanism is associated with production of IFN-γ, a pro-inflammatory cytokine mainly produced by NK cells following IL-15 SA stimulation.