title: 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.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55906, USA.
authors.forename: Ashenafi Y
authors.initials: AY
authors.lastname: Tilahun
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Karau
authors.forename: Chad R
authors.initials: CR
authors.lastname: Clark
authors.forename: Robin
authors.initials: R
authors.lastname: Patel
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D018089:Superantigens / Q000276:immunology*; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D004768:Enterotoxins; D015803:HLA-DR3 Antigen; D007166:Immunosuppressive Agents; D018089:Superantigens; D016559:Tacrolimus