Grant: Project Grant

Sepsis is the major worldwide cause of death in intensive care units typically amongst the very young, the elderly and in immune-compromised patients following infection. Sepsis arises when a patient mounts an overwhelming immune response to an infection. If not treated quickly, 30% to 50% of patients will succumb to sepsis. In Canada, one in 18 Canadian deaths was attributed to sepsis in 2011. With an aging population and the rise in Canadians being exposed to old and new pathogens, sepsis is projected to become one of the top leading cause of death in this country in the next decades. Clinical interventions aimed at treating sepsis and septic shock [with antibiotics and other therapies] have not led to a significant enhancement in patient survival, unless performed soon after diagnosis. There is thus a need to develop new therapeutic agents to rapidly restore dysfunctional immune responses observed during sepsis. Here, we propose to develop protein-based immune modulators that will potentially re-stabilize immune responses in these patients by first dampening the patient's initial excessive inflammatory response to a pathogen without causing a persistent immune suppression event that may leave the patient susceptible to other infections. We have recently worked on 2 distinct immune suppressive pathways (CD200:CD200R1; VISTA:VISTAR) that act on the first line of immune defense towards pathogens. Importantly, we have recently designed a protein bispecific (carries two functions) that incorporates the active parts of both VISTA and CD200 and shown that this agent can strongly dampened the initial burst of immune mediators produced by activated mouse immune cells that can lead to sepsis. We now propose to further study our most active protein bispecific and design new and more potent ones with a view to monitor all arms of the immune system affected during sepsis and by our bispecifics. This research may lead to off-the-shelf biologics to control sepsis in patients.