Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation

Sriskandan, Shiranee; Ferguson, Melissa; Elliot, Victoria; Faulkner, Lee; Cohen, Jonathan

doi:10.1093/jac/dkl173

Cited by 77 publications

(58 citation statements)

References 28 publications

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“…Many of these have sought to prevent or disrupt the formation of MHC-II/SAg/TCR complexes. These have ranged from explorations of active immunization with inactivated recombinant SEB vaccines (5, 26, 52), synthetic peptides (53), and proteasome-SEB toxoid combinations (29,30) to investigations of antibody-based passive immunoprophylaxis/immunotherapy (9,10,21,23,38,49), as well as synthetic peptides antagonists (1-3) and receptor mimics such as chimeric mimics of MHC-II-TCR (19,27,36) and of the TCR V␤ (7). Although all of these approaches have shown some promise, based on the long history of clinical experience with the use of antibodies, our approach has focused on demonstration of an approach to the derivation of forms of monoclonal anti-SEB antibodies that might be suitable for clinical use.…”

Section: Discussionmentioning

confidence: 99%

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

et al. 2010

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Staphylococcal enterotoxin B (SEB), a shock-inducing exotoxin synthesized by Staphylococcus aureus, is an important cause of food poisoning and is a class B bioterrorism agent. SEB mediates antigen-independent activation of a major subset of the T-cell population by cross-linking T-cell receptors (TCRs) with class II major histocompatibility complex (MHC-II) molecules of antigen-presenting cells, resulting in the induction of antigen independent proliferation and cytokine secretion by a significant fraction of the T-cell population. Neutralizing antibodies inhibit SEB-mediated T-cell activation by blocking the toxin's interaction with the TCR or MHC-II and provide protection against the debilitating effects of this superantigen. We derived and searched a set of monoclonal mouse anti-SEB antibodies to identify neutralizing anti-SEB antibodies that bind to different sites on the toxin. A pair of non-cross-reactive, neutralizing anti-SEB monoclonal antibodies (MAbs) was found, and a combination of these antibodies inhibited SEB-induced T-cell proliferation in a synergistic rather than merely additive manner. In order to engineer antibodies more suitable than mouse MAbs for use in humans, the genes encoding the VL and VH gene segments of a synergistically acting pair of mouse MAbs were grafted, respectively, onto genes encoding the constant regions of human Ig and human IgG1, transfected into mammalian cells, and used to generate chimeric versions of these antibodies that had affinity and neutralization profiles essentially identical to their mouse counterparts. When tested in cultures of human peripheral blood mononuclear cells or splenocytes derived from HLA-DR3 transgenic mice, the chimeric human-mouse antibodies synergistically neutralized SEB-induced T-cell activation and cytokine production.

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Section: Discussionmentioning

confidence: 99%

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

et al. 2010

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“…More recently the successful use of polyclonal human intravenous immunoglobulin (IVIG) for the treatment of invasive infections has been demonstrated in numerous in vitro studies [12,[115][116][117][118]. However, the use of IVIG as an adjunctive treatment in a clinical setting has been less promising [119,120].…”

Section: Novel Therapeutics For the Treatment Of Invasive S Pyogenesmentioning

confidence: 99%

The Role of Streptokinase as a Virulence Determinant of Streptococcus pyogenes – Potential for Therapeutic Targeting

McArthur

Cook²,

Venturini³

et al. 2012

CDT

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. (2012). The role of streptokinase as a virulence determinant of streptococcus pyogenes -potential for therapeutic targeting. Current Drug Targets, 13 (3), 297-307. The role of streptokinase as a virulence determinant of streptococcus pyogenes -potential for therapeutic targeting AbstractStreptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome. These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein. Here, we describe the role of streptokinase in invasive pathogenesis and discuss some potentially useful strategies for disruption of streptokinase mediated plasminogen activation which could be employed to treat severe invasive S. pyogenes infections. AbstractStreptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome.These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein.Here, we describe the role of streptokinase in invasive pathogenesis and discuss some potentially useful strategies that disrupt streptokinase mediated plasminogen activation and could be employed to treat severe invasive S. pyogenes infections.3

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“…The advent of the HLA class II transgenic (HLA-tg) mice provided an opportunity to study the pathogenesis of GAS in a readily manipulated animal model with a sensitivity to SAgs similar to that of humans (22)(23)(24)(25)(26). Indeed, several studies have shown that HLA-tg mice mount potent responses to GAS SAgs (20,23,25,27,28).…”

mentioning

confidence: 99%

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

Nooh

El-Gengehi

Kansal

et al. 2007

The Journal of Immunology

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Our epidemiologic studies on invasive Group A Streptococci (GAS) infections identified specific HLA class II haplotypes/alleles conferring high-risk or protection from streptococcal toxic shock syndrome with a strong protection conferred by the DRB1*15/DQB1*06 haplotype. We used HLA-transgenic mice to provide an in vitro and in vivo validation for the direct role of HLA class II allelic variation in streptococcal toxic shock syndrome. When splenocytes from mice expressing the protective HLA-DQB1*06 (DQ6) allele were stimulated with a mixture of streptococcal superantigens (SAgs), secreted by the prevalent M1T1 strain, both proliferative and cytokine responses were significantly lower than those of splenocytes from mice expressing the neutral DRB1*0402/DQB1*0302 (DR4/DQ8) alleles (p < 0.001). In crisscross experiments, the presentation of SAgs to pure T cells from either the DQ6 or the DR4/DQ8 mice resulted in significantly different levels of response depending on the HLA type expressed on the APCs. Presentation by HLA-DQ6 APCs elicited significantly lower responses than the presentation by HLA-DR4/DQ8 APCs. Our in vitro data were supported by in vivo findings, as the DQ6 mice showed significantly longer survival post-i.v. infection with live M1T1 GAS (p < 0.001) and lower inflammatory cytokine responses as compared with the DR4/DQ8 mice (p < 0.01). The data presented here provide evidence for a direct role of HLA class II molecules in modulating responses to GAS SAgs and underscore the dominant role of HLA class II allelic variation in potentiating the severity of GAS systemic infections.

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Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation

Abstract: IVIG monotherapy can confer benefit in experimental streptococcal shock, but extension of these findings to the clinical situation will require further evaluation.

Cited by 77 publications

References 28 publications

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

Potent Neutralization of Staphylococcal Enterotoxin B by Synergistic Action of Chimeric Antibodies

The Role of Streptokinase as a Virulence Determinant of Streptococcus pyogenes – Potential for Therapeutic Targeting

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

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