Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with chronic renal failure on hemodialysis treatment.
BACKGROUND
Many cases of patients with chronic renal failure (CRF) on hemodialysis are known to be infected with Staphylococcus aureus (S. aureus) from the sites of blood vessel puncture for hemodialysis and the custody of the vascular access catheter. S. aureus produces superantigens, such as toxic shock syndrome toxin-1 (TSST-1), which may influence the sensitivity of peripheral-blood mononuclear cells (PBMCs) to immunosuppressive drugs after they are received postrenal transplantation.


METHODS
We examined the drug-sensitivities of PBMCs stimulated with TSST-1 in 18 CRF patients on hemodialysis. PBMCs were isolated from venous blood before hemodialysis, and were cultured in the presence of concanavalin A (ConA) or TSST-1 and serial concentrations of the drugs. In vitro drug concentrations giving 50% inhibition (IC(50)) of PBMC blastogenesis were calculated. INF-gamma and IL-4 in supernatants of cultured PBMCs were measured with ELISA.


RESULTS
The median (range) IC(50) values (ng/ml) for four drugs; tacrolimus, cyclosporine, methylprednisolone, and prednisolone, evaluated in ConA-stimulated PBMCs of CRF patients were 0.04 ng/ml (0.03-0.21), 3.0 (0.1-15.1), 3.0 (1-104), and 16.2 (5.9-35.4), respectively. The values for the four drugs evaluated in TSST-1-stimulated PBMCs were 0.22 (0.08-0.36), 18.9 (5.1-38.2), 328.3 (1.9-1000), and 150.9 (94.7-880), respectively, which were significantly higher than those evaluated in the ConA-stimulated PBMCs (p=0.003-0.023). Amounts of INF-gamma and IL-4 produced from cells were not significantly different between the ConA-or TSST-1-stimulated PBMCs in the presence or absence of immunosuppressive drugs.


CONCLUSIONS
These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in CRF patients after renal transplantation. Furthermore, INF-gamma and IL-4 related pathways appear not to play major roles in the TSST-1-induced attenuation of the drug sensitivities.
Konno
Osamu
O
5th Department of Surgery, Hachioji Medical Center, Tokyo Medical University, Japan. kosa@zg7.so-net.ne.jp
Hirano
Toshihiko
T
Katsuyama
Kanako
K
Oka
Kitaro
K
Matsuno
Naoto
N
Nagao
Takeshi
T
D000368:Aged; D001427:Bacterial Toxins / Q000378:metabolism*; D019703:Calcineurin / Q000494:pharmacology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007371:Interferon-gamma / Q000096:biosynthesis / Q000187:drug effects; D015847:Interleukin-4 / Q000096:biosynthesis; D007676:Kidney Failure, Chronic / Q000150:complications / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011239:Prednisolone / Q000494:pharmacology; D006435:Renal Dialysis / Q000009:adverse effects; D013203:Staphylococcal Infections / Q000209:etiology; D018089:Superantigens / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology
D001427:Bacterial Toxins; D004768:Enterotoxins; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine; D011239:Prednisolone; D019703:Calcineurin; D016559:Tacrolimus; D008775:Methylprednisolone