title: Chimeric anti-staphylococcal enterotoxin B antibodies and lovastatin act synergistically to provide in vivo protection against lethal doses of SEB.
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.
authors.affiliation: Department of Biology, Amherst College, Amherst, Massachusetts, United States of America.
authors.forename: Mulualem E
authors.initials: ME
authors.lastname: Tilahun
authors.forename: Alan
authors.initials: A
authors.lastname: Kwan
authors.forename: Kannan
authors.initials: K
authors.lastname: Natarajan
authors.forename: Megan
authors.initials: M
authors.lastname: Quinn
authors.forename: Ashenafi Y
authors.initials: AY
authors.lastname: Tilahun
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.forename: David H
authors.initials: DH
authors.lastname: Margulies
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Osborne
authors.forename: Richard A
authors.initials: RA
authors.lastname: Goldsby
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D004357:Drug Synergism; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D008148:Lovastatin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012772:Shock, Septic / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018089:Superantigens / Q000276:immunology; D015996:Survival Rate
chemical_list: D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000924:Anticholesteremic Agents; D004768:Enterotoxins; D015803:HLA-DR3 Antigen; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D008148:Lovastatin
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