Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single proinflammatory mediators have failed to improve survival in
sepsis and aseptic systemic inflammatory response syndromes. This failure could be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this storm. Licensed pooled
intravenous immunoglobulin preparations seemed to be a promising candidate, but they have also failed in their present form to prevent
sepsis-related death. We report here the protective effect of a single dose of
intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of
sepsis and aseptic systemic
inflammation. The modification of the pooled
immunoglobulin G molecules by exposure to ferrous
ions resulted in their newly acquired ability to bind some proinflammatory molecules,
complement components and endogenous "danger" signals. The improved survival in
endotoxemia was associated with serum levels of proinflammatory
cytokines, diminished
complement consumption and normalization of the coagulation time. We suggest that
intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in
sepsis and related systemic inflammatory syndromes.