The initial phase of
sepsis is characterized by massive inflammatory
cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating
cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of
cytokine production in innate immunity. The purpose of this study was to determine the role for OX40-OX40
ligand (OX40L) interaction in the innate immune response to polymicrobial
sepsis. Humans with
sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial
sepsis, a direct role for OX40L in regulating
inflammation was indicated by improved survival, decreased
cytokine production, and a decrease in remote organ damage in OX40L(-/-) mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in
sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in
sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1(-/-) mice further confirms a T cell-independent role for OX40L stimulation in
sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial
sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.