Abstract
Staphylococcal enterotoxin B (SEB) is one of a family of toxins secreted by Staphylococcus aureus that act as superantigens, activating a large fraction of the T-cell population and inducing production of high levels of inflammatory cytokines that can cause toxic shock syndrome (TSS) and death. Extracellular engagement of the TCR of T-cells and class II MHC of antigen presenting cells by SEB triggers the activation of many intracellular signaling processes. We engineered chimeric antibodies to block the extracellular engagement of cellular receptors by SEB and used a statin to inhibit intracellular signaling. Chimeric human-mouse antibodies directed against different neutralizing epitopes of SEB synergistically inhibited its activation of human T-cells in vitro. In the in vivo model of lethal toxic shock syndrome (TSS) in HLA-DR3 transgenic mice, two of these antibodies conferred significant partial protection when administered individually, but offered complete protection in a synergistic manner when given together. Similarly, in vivo, lovastatin alone conferred only partial protection from TSS similar to single anti-SEB antibodies. However, used in combination with one chimeric neutralizing anti-SEB antibody, lovastatin provided complete protection against lethal TSS in HLA-DR3 transgenic mice. These experiments demonstrate that in vivo protection against lethal doses of SEB can be achieved by a statin of proven clinical safety and chimeric human-mouse antibodies, agents now widely used and known to be of low immunogenicity in human hosts.
Highlights
Staphylococcal enterotoxin B (SEB) is a potent exotoxin secreted by Staphylococcus aureus that causes life-threatening toxic shock syndrome (TSS) [1,2,3,4,5] and food poisoning [6]
We identified a pair of high affinity, noncrossreacting, and SEB-neutralizing mouse monoclonal antibodies (MAbs) and converted these antibodies into the mouse-human chimeric antibodies, Ch 82 M and Ch 63 [40]
When we tested the SEBneutralization efficiency of these chimeric antibodies in vitro in splenocyte cultures derived from HLA-DR3 transgenic nice, a more demanding and humanlike model system [35,36,37,49] as well as in human PBMCs, a combination of Ch 82 M and Ch 63 produced a greater neutralization of SEB than equivalent amounts of either 82 M or Ch 63 acting alone [40]
Summary
Staphylococcal enterotoxin B (SEB) is a potent exotoxin secreted by Staphylococcus aureus that causes life-threatening toxic shock syndrome (TSS) [1,2,3,4,5] and food poisoning [6]. Engineered mimics of TCR Vb [32] that block SEB activation in vitro and show promising results when tested in vivo in a rabbit model have been reported [32] These mimics were reported to have short half-lives (325 minutes in rabbits) and their test in human MHC-II transgenics, a robust animal model that mimics human TSS [33,34,35,36,37,38] has not yet been reported. Despite these efforts, at present there is no curative treatment for SEB-induced TSS, no practical prophylaxis and no antidote for intoxication following accidental or malicious exposure. The mortality rate varies from 4 to 22% and clinical treatment is currently focused on supportive measures, targeted antibiotic therapy, and adjunctive immunomodulatory therapy [39]
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