Novel Hybrid Growth Factor for Immune Reconstitution in Sepsis Sepsis is a major clinical problem with more than a 40% mortality rate, and is the leading cause of death in intensive care units. Despite a great deal of investment of time and money in basic and clinical research including more than 40 clinical trials, there is no FDA-approved drug for sepsis. Historically, experimental sepsis treatments focused on the early phase which consists of a systemic inflammatory response syndrome (SIRS) characterized by excessive production of pro-inflammatory mediators by immune cells. Although experimental treatment modalities targeting inflammatory mediators (e.g. TNF-a or IL-1) were often effective in animal models, they failed in human clinical trials. It is now understood that following the early acute phase, there is a transition to a compensatory anti-inflammatory response syndrome (CARS) to limit damage, leading to immunosuppression and promotion of chronic infection . In the chronic phase of sepsis, patients have profound deficiencies in innate and adaptive immune responses and mortality is associated with persistent and or secondary infections. Therefore, a new paradigm of sepsis treatment focuses on the use of immunostimulating agents. The goal of this proposal is to develop a novel hybrid bifunctional cytokine called Ha7 to promote immune reconstitution in sepsis patients. Ha7 is a novel therapeutic approach designed to restore immune cell populations and function as well as protect from multiorgan failure. Ha7 consists of IL-7 linked to the a chain of hepatocyte growth factor (HGF). To improve stability and extend in vivo half-life each cytokine is fused to the Fc of IgG molecules that are modified to promote the formation of heterodimers during mammalian cell expression. Ha7 will initially be tested for toxicity in mice. The therapeutic efficacy of Ha7 will be evaluated in the cecal ligation and puncture (CLP) model of sepsis-induced immune suppression in mice. Mice treated with CLP and Ha7 will be evaluated for restoration of normal numbers of T lymphocytes, dendritic cells (DC) and their function such as cytokine production in response to in vitro stimulation. The ability of DCs to induce an allogeneic response and stimulate IL-2 production will be tested in culture. The ability of Ha7 therapy to restore the delayed type hypersensitivity response in immunosuppressed mice following CLP will be evaluated in vivo. Ha7 will be tested in a lethal CLP model to determine if it can promote survival. The results of these studies will pave the way for submission of an IND in future work. The unique dual mechanism of action of Ha7 will provide a new therapeutic option potentially superior to the relatively limited and ineffective current treatments for patients diagnosed in the immunosuppressive phase of sepsis.
