This project is focused on examining the ability of immune therapy to reverse the impairment in host immune function that occurs in protracted sepsis. Sepsis is the most common cause of death in most intensive care units and the 10th leading cause of overall mortality in the United States. Although early deaths in sepsis are often due to excessive inflammation, sepsis evolves to a highly immunosuppressive state. The underlying hypothesis of the present proposal is that many of the deaths occurring later in the course of sepsis are due to the resultant immunosuppression and that therapy that augments host immunity will improve survival. This application examines two novel drug candidates, i.e., IL-7 and anti-programmed cell death one (PD-1) as potential immune enhancing therapies of sepsis. IL-7 is cytokine that acts at numerous levels to improve host immunity. Its major actions are on CD4 and CD8 T cells. IL-7 has shown efficacy in viral, bacterial, and fungal infections. A second immunotherapeutic agent that will be tested is anti-PD-1 antibody. PD-1 is a cell receptor that is upregulated on lymphocytes in sepsis and causes inhibition of cell function. Antibodies to PD-1 have improved survival in several infectious models. IL-7 and anti-PD-1 antibody will be tested for their ability to improve survival in clinically relevant animal models f sepsis. In addition, studies will also examine the ability of IL-7 and anti-PD-1 to improve white blood cell function in septic patients. The results of this project will lead to a better understanding of host immunity in sepsis and may provide insight into potential therapies of this highly lethal disorder.

Public Health Relevance

This proposal tests the ability of drugs which boost the immune system to improve survival in animal models of severe infection. This project also investigates ability of these drugs to improve function of white blood cells from critically ill patients with life threatening infection.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Hutchins, Noelle A; Unsinger, Jacqueline; Hotchkiss, Richard S et al. (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224-33
Venet, Fabienne; Lukaszewicz, Anne-Claire; Payen, Didier et al. (2013) Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol 25:477-83
Scatizzi, John C; Hutcheson, Jack; Pope, Richard M et al. (2010) Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis. Arthritis Rheum 62:441-51
McDunn, Jonathan E; Muenzer, Jared T; Dunne, Benjamin et al. (2009) An anti-apoptotic peptide improves survival in lethal total body irradiation. Biochem Biophys Res Commun 382:657-62
Peck-Palmer, Octavia M; Unsinger, Jacqueline; Chang, Katherine C et al. (2009) Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages. Shock 31:359-66
McDunn, Jonathan E; Muenzer, Jared T; Rachdi, Latif et al. (2008) Peptide-mediated activation of Akt and extracellular regulated kinase signaling prevents lymphocyte apoptosis. FASEB J 22:561-8
Schwulst, Steven J; Davis, Christopher G; Coopersmith, Craig M et al. (2007) Adoptive transfer of dying cells causes bystander-induced apoptosis. Biochem Biophys Res Commun 353:780-5
Hotchkiss, R; Nunnally, I; Lindquist, S et al. (1993) Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol 265:R1447-57