No abstract

The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.

Material

Recently, we showed that antibodies catalyze the generation of hydrogen peroxide (H2O2) from singlet molecular oxygen (1O2*) and water. Here, we show that this process can lead to efficient killing of bacteria, regardless of the antigen specificity of the antibody. H2O2 production by antibodies alone was found to be not sufficient for bacterial killing. Our studies suggested that the antibody-catalyzed water-oxidation pathway produced an additional molecular species with a chemical signature similar to that of ozone. This species is also generated during the oxidative burst of activated human neutrophils and during inflammation. These observations suggest that alternative pathways may exist for biological killing of bacteria that are mediated by potent oxidants previously unknown to biology.

There is increasing recognition that a major pathophysiologic event in sepsis is the progression to an immunosuppressive state in which the host is unable to eradicate invading pathogens. Although there are likely numerous causes for the immunosuppression, expression of negative costimulatory molecules on immune effector cells is a likely contributing factor. PD-1 is a recently described, negative costimulatory molecule that has potent effects to inhibit T cell activation, cytokine production, and cytotoxic functions. PD-1 plays a critical role in the host response to specific pathogens, but relatively little work has been done on the possible effects of PD-1 in sepsis. We hypothesized that the anti-PD-1 antibody would improve survival in sepsis. Mice underwent CLP, and PD-1 expression was quantitated. Additionally, the effects of anti-PD-1 antibody on lymphocyte apoptosis, cytokine production, host immunity, and survival were determined. PD-1 expression increased beginning 48 h after sepsis, and >20% of CD4 and CD8 T cells were positive by 7 days. Anti-PD-1 antibody administered 24 h after sepsis prevented sepsis-induced depletion of lymphocytes and DCs, increased Bcl-xL, blocked apoptosis, and improved survival. Anti-PD-1 also prevented the loss in DTH, a key indicator of immunocompetence in sepsis. Thus, delayed administration of anti-PD-1 antibody, an important therapeutic advantage, was effective in sepsis. Furthermore, these results add to the growing body of evidence that modulation of the positive and negative costimulatory pathways on immune cells represents a viable therapeutic approach in reversing immunosuppression and improving sepsis survival.