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. online address: http://www.molmed.org

Enhanced Pro-apoptotic Effects of Fe(II)-Modified IVIG on Human Neutrophils

“…A special maltose-and albumin-free batch of Immunoveninintact produced without incubation at acidic pH (BulBio-NCIPB Ltd., Sofia, Bulgaria) was used, as previously done (21). Further IVIG preparations included KIOVIG TM (Shire Switzerland GmbH), Intratect R (Biotest (Schweiz) AG), Endobulin S/D (Baxter, Deerfield IL, USA) and Octagam 10% (Octapharm, Lachen, Switzerland).…”

“…Further IVIG preparations included KIOVIG TM (Shire Switzerland GmbH), Intratect R (Biotest (Schweiz) AG), Endobulin S/D (Baxter, Deerfield IL, USA) and Octagam 10% (Octapharm, Lachen, Switzerland). Modification with protein-destabilizing agents was performed as previously described (19)(20)(21)26). Briefly, for modification with pH4, native Immunovenin-intact (10 mg/ml) was incubated 5 min at room temperature in 0.1 M sodium acetate buffer (Sigma-Aldrich, St. Louis MO, USA).…”

“…Co-factors, such as ferrous ions, reactive oxygen species and heme have been shown to broaden the specificities of immunoglobulins (19,20). IVIG modified by ferrous ions or heme showed superior therapeutic effects in various in vivo models of sepsis (21)(22)(23) or autoimmune diabetes (24).…”

Accelerated Orthodontics

“…Recently intravenous immunoglobulin (IVIg) preparations which are used in immunodeficient patients as replacement therapy. These preparations have been shown to induce COX-2 mediated PGE 2 and cytokine production [14,15]. Future potential of these preparations could be used to modulate orthodontic movement via PGE 2 synthesis.…”

The Potential Use of Pharmacological Agents to Modulate Orthodontic Tooth Movement (OTM)

“…Intravenous immunoglobulin (IVIg) preparations are polyspecific and polyclonal immunoglobulin therapeutic preparations used as a replacement therapy in immunodeficient patients (Grader-Beck et al, 2011 ; Schneider et al, 2015 ). These IVIg preparations were shown to induce COX-2 mediated PGE2 synthesis and cytokine production (Trinath et al, 2013 ; von Gunten et al, 2013 ; Djoumerska-Alexieva et al, 2015 ). It is possible that local administration of these IVIg preparations could be used to modulate bone modeling through PEG2 induction and bypass some of the limitations of PEG2 injections.…”