title: Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes.
abstract: 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.
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Iglika
authors.initials: I
authors.lastname: Djoumerska-Alexieva
authors.affiliation: INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Lubka
authors.initials: L
authors.lastname: Roumenina
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Anastas
authors.initials: A
authors.lastname: Pashov
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.|INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Jordan
authors.initials: J
authors.lastname: Dimitrov
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Maya
authors.initials: M
authors.lastname: Hadzhieva
authors.affiliation: Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Sandro
authors.initials: S
authors.lastname: Lindig
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Elisaveta
authors.initials: E
authors.lastname: Voynova
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Petya
authors.initials: P
authors.lastname: Dimitrova
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Nina
authors.initials: N
authors.lastname: Ivanovska
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Bockmeyer
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Zvetanka
authors.initials: Z
authors.lastname: Stefanova
authors.affiliation: Cytokines and Inflammation Unit, Institut Pasteur, Paris, France; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.affiliation: Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bläss
authors.affiliation: Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Claus
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Gunten
authors.affiliation: INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Srini
authors.initials: S
authors.lastname: Kaveri
authors.affiliation: Cytokines and Inflammation Unit, Institut Pasteur, Paris, France; and.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.affiliation: Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Department of Immunology, Stefan Angelov Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.|Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Tchavdar
authors.initials: T
authors.lastname: Vassilev