title: Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with antineutrophil cytoplasmic antibody-associated vasculitis and nephrosis.
abstract: Successful immunosuppressive therapy is critical for the treatment of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and nephrosis. However, a considerable number of patients have shown clinical resistance to therapy. Bacterial infection might influence the clinical response of patients to immunosuppressive drugs, but few studies have been carried out to investigate the effect of bacterial superantigens on the efficacy of the drugs in these patients. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the blastogenesis of PBMCs obtained from 12 ANCA-associated vasculitis patients (ANCA patients), eight patients with nephrotic syndrome, and eight healthy subjects. PBMC-stimulation index was calculated from the formula: [3H]thymidine incorporated in the presence of stimulant (dpm)/[3H]thymidine incorporated in the absence of stimulant (dpm). In vitro drug concentrations giving 50% inhibition (IC50s) of PBMC blastogenesis stimulated with concanavalin A (con A) or toxic shock syndrome toxin 1 (TSST-1) derived from Staphylococcus aureus (S. aureus) were calculated. The IC50 values for the four drugs evaluated in TSST-1-stimulated PBMCs were significantly higher than those evaluated in con A-stimulated PBMCs in both ANCA patients and nephrosis patients (p<0.012-0.044). Whereas, the IC50 values for these immunosuppressive drugs, except methylprednisolone, were not significantly different between con A- and TSST-1-stimulated PBMCs in healthy subjects. The stimulation index was not significantly different between the con A- and TSST-1-stimulated PBMCs in either of the subject groups. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in ANCA patients and nephrosis patients.
authors.affiliation: Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. hiranot@ps.toyaku.ac.jp
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hirano
authors.forename: Hisayo
authors.initials: H
authors.lastname: Fukushima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Noriko
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kitaro
authors.initials: K
authors.lastname: Oka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D001427:Bacterial Toxins / Q000494:pharmacology*; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D009401:Nephrosis / Q000097:blood / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology; D018089:Superantigens / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology; D014657:Vasculitis / Q000097:blood / Q000473:pathology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001427:Bacterial Toxins; D065095:Calcineurin Inhibitors; D004768:Enterotoxins; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D003208:Concanavalin A; D016572:Cyclosporine; D011239:Prednisolone; D016559:Tacrolimus; D008775:Methylprednisolone