Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes
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.
This work was supported by grants from the Bulgarian-Swiss Research Programme (BSRP IZEBZO_142967), the Bulgarian National Science Fund (DFNI B02/29), the Pasteur Institute (ACIP A07-2012), the NATO Science for Peace Program (SfP 982158), and the German Federal Ministry of Education and Research (BMBF; grant 01EO1002) and grant 03Z2J521 (Meta-ZIK), both to the Centre for Sepsis Control and Care. We thank D Himsel for technical assistance.
The microarray data generated in this publication have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through the accession number GSE55964.
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