Protein destabilizing agents induce polyreactivity and enhanced immunomodulatory activity in IVIg preparations

Djoumerska-Alexieva, Iglika; Dimitrov, Jordan D.; Nacheva, Julia; Kaveri, Srini V.; Vassilev, Tchavdar

doi:10.1080/08916930902832181

Cited by 12 publications

(14 citation statements)

References 7 publications

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“…We previously reported that cyclophosphamidesensitive CD4+FoxpY cells (Tregs) are at least partially responsible for the protective effects of heme-exposed IVIg used in doses of 200-600 mg/kg in animals with MLD-STZ diabetes (14). A recent study showed that a single dose of Fe(II)-exposuremodified IVIg prevented the death of mice with experimental septic shock, induced by the injection of bacterial lipopolysaccharide or oflive Escherichia coli, while the native preparation failed to do so (8,9). In the present study, we show that exposure to ferrous ions increased anti-diabetogenic effects of IVIgs and decreased its therapeutic dose.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the spectrum ofantigens, bound by a single antibody, could be modified by some physical or chemical agents -the so called "induced polyspecificity," which is not a laboratory artifact, but can also be observed in vivo (7). It was therefore postulated that transient exposure of some IgG molecules to protein-destabilizing agents may lead to a significant expansion of the spectrum of recognized epitopes without their concomitant denaturation (8)(9)(10)(11)(12).…”

Section: Intravenousmentioning

confidence: 99%

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Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

et al. 2014

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The aim of this study was to investigate the immunomodulatory capacity of native and Fe(II)-exposed intravenous immune globulin (IVIg) in multiple low dose streptozotocin-induced diabetes and to delineate the mechanisms of their influence on immune cell functions. Optimal doses (200-600mgl kg) of IVlg prevented the development of hyperglycemia, glycosuria and attenuated mononuclear cell infiltration in pancreatic islets. Fe(II) exposure of IVlg decreased their optimal therapeutic dose to 100mg/kg which significantly decreased the serum levels of proinflammatory cytokines compared to the same dose of native IVlg. This was accompanied by lower numbers of TNF-a, IFN-y and IL-17 producing CD4+ T cells and increased frequencies of CD4+IL-I0+and CD4+IL-4+ T cells in the pancreatic lymph nodes and islets on day 16 after diabetes induction. Ferrous ion-exposed IVlg enhanced the bias towards Th2 response while the regulatory Foxp.l" T cells were not affected.

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Section: Discussionmentioning

confidence: 99%

Section: Intravenousmentioning

confidence: 99%

Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

et al. 2014

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“…The molecular composition of pooled IgG exposed to ferrous ions did not differ from that of the native preparation as shown by size-exclusion analyses performed by HPLC. 71 2. The presence of aggregated IgG after ferrous ions exposure was also ruled out by the fact that modified IgG do not cause activation of the complement as shown by the test according to Pharmacopoeia requirements for pooled therapeutic IVIG (unpublished data).…”

Section: Of Antigen-bindingmentioning

confidence: 99%

Antibody Polyspecificity

Dimitrov

Pashov

Vassilev

2012

Advances in Experimental Medicine and Biology

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Polyspecificity (polyreactivity) is currently considered an intrinsic property of a subset of antibodies, primarily of naturally occurring autoantibodies. Polyspecificity is no longer viewed as a biologically irrelevant stickiness. Furthermore, the capacity to bind defined sets of unrelated antigens finds its structural explanation. What is most intriguing, the elucidation of the role of polyspecificity may promote a better understanding of specific recognition as a function of the entire immune system. The early events of immune recognition depend on polyspecific binding. Thus, the completeness of the naïve repertoires of antigen receptors is ensured. The process of immunologically-relevant antigen recognition that is initiated goes beyond simple molecular interaction with the antigenic determinants. It involves cellular cooperation and culminates in antibody response maturation. Recent findings also pave the way for the clinical application of posttranslationally induced polyspecificity.

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“…Previous studies by our group and others have proven that, in addition to low pH buffers, the exposure to a number of other substances (for example, ferrous ions, heme, reactive oxygen species, and so on) also increases the antigen-binding polyspecificity of some IgG molecules (5,(15)(16)(17). IVIg modified by Fe(II) exposure could bind to the human proinflammatory cytokine interferon (IFN)-γ and could improve survival in mice injected intravenously with 5 × 10 8 live Escherichia coli or intraperitoneally with bacterial LPS (15,18). Infusions of ferrous ion-modified IVIg were also shown dilutions of the respective cytokines and incubated for 1 h at 37°C following the manufacturer's protocol.…”

Section: Materials and Methods Micementioning

confidence: 99%

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes

Djoumerska-Alexieva

Roumenina

Pashov

et al. 2015

Mol Med

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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

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Protein destabilizing agents induce polyreactivity and enhanced immunomodulatory activity in IVIg preparations

Cited by 12 publications

References 7 publications

Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

Enhanced Anti-Diabetogenic Effect of Intravenous Immune Globulin Modified by Ferrous Ion Exposure

Antibody Polyspecificity

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes

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