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Bacterial Superantigen Toxins, CD28, and Drug Development

During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate...

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Detalles Bibliográficos
Autor principal: Kaempfer, Raymond
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265702/
https://www.ncbi.nlm.nih.gov/pubmed/30404186
http://dx.doi.org/10.3390/toxins10110459
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author Kaempfer, Raymond
author_facet Kaempfer, Raymond
author_sort Kaempfer, Raymond
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description During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant.
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spelling pubmed-62657022018-12-07 Bacterial Superantigen Toxins, CD28, and Drug Development Kaempfer, Raymond Toxins (Basel) Review During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant. MDPI 2018-11-06 /pmc/articles/PMC6265702/ /pubmed/30404186 http://dx.doi.org/10.3390/toxins10110459 Text en © 2018 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Kaempfer, Raymond
Bacterial Superantigen Toxins, CD28, and Drug Development
title Bacterial Superantigen Toxins, CD28, and Drug Development
title_full Bacterial Superantigen Toxins, CD28, and Drug Development
title_fullStr Bacterial Superantigen Toxins, CD28, and Drug Development
title_full_unstemmed Bacterial Superantigen Toxins, CD28, and Drug Development
title_short Bacterial Superantigen Toxins, CD28, and Drug Development
title_sort bacterial superantigen toxins, cd28, and drug development
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265702/
https://www.ncbi.nlm.nih.gov/pubmed/30404186
http://dx.doi.org/10.3390/toxins10110459
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