The impact of tacrolimus on the immunopathogenesis of staphylococcal enterotoxin-induced systemic inflammatory response syndrome and pneumonia.

Abstract

Staphylococcal superantigens (SAg) are a family of potent exotoxins produced by Staphylococcus aureus. They play an important role in the pathogenesis of staphylococcal shock and pneumonia by causing a robust activation of the immune system and eliciting a strong surge in systemic cytokine and chemokine levels. Given the biological functions of SAg, we evaluated the efficacy of tacrolimus, a potent immunosuppressive agent, in the prophylaxis and therapy of staphylococcal TSS and pneumonia using human leukocyte antigen (HLA)-DR3 transgenic mice. Tacrolimus significantly inhibited staphylococcal SAg induced T cell activation in vitro. In vivo, tacrolimus significantly suppressed the SAg-induced elevation in serum cytokine and chemokine levels when given prophylactically, when administered immediately or even 2 h following systemic SAg challenge. Paradoxically, neither the prophylactic nor post-exposure treatment with tacrolimus protected mice from lethal SAg-induced TSS. A closer examination revealed that tacrolimus failed to suppress SAg-induced T cell proliferation and systemic pathology, including gut dysfunction. Tacrolimus also failed to protect from lethal pneumonia induced by a SAg-producing S. aureus strain. Thus, our study showed that even though T cell activation by SAg plays a major role in the immunopathogenesis of TSS and pneumonia, tacrolimus alone has no beneficial effect.

• Authors: Ashenafi Y Tilahun, Melissa J Karau, Chad R Clark, Robin Patel, Govindarajan Rajagopalan
• Journal: Microbes and infection (Microbes Infect) Vol. 14 Issue 6 Pg. 528-36 (Jun 2012) ISSN: 1769-714X [Electronic] France
• PMID: 22273732 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Chemical References

• Cytokines
• Enterotoxins
• HLA-DR3 Antigen
• Immunosuppressive Agents
• Superantigens
• Tacrolimus

Topics

• Animals
• Cytokines (biosynthesis, immunology)
• Enterotoxins (immunology)
• HLA-DR3 Antigen (genetics)
• Humans
• Immunosuppressive Agents (pharmacology, therapeutic use)
• Lymphocyte Activation (drug effects)
• Mice
• Mice, Transgenic
• Pneumonia, Staphylococcal (drug therapy, immunology, physiopathology)
• Staphylococcus aureus (drug effects, pathogenicity)
• Superantigens (immunology)
• Systemic Inflammatory Response Syndrome (drug therapy, immunology, physiopathology)
• T-Lymphocytes (immunology)
• Tacrolimus (pharmacology, therapeutic use)
• Treatment Outcome