Immunosuppressive activity of fosfomycin on human T-lymphocyte function in vitro

Abstract

Recent investigations have shown that some antibiotics also work as immunomodulators. We have recently reported that fosfomycin (FOM) has an immunomodulatory effect on human B-cell activation. FOM is a unique antibiotic which is chemically unrelated to any other known antibacterial agent. In the present study, we examined the effect of FOM on human T-cell function. FOM inhibited the proliferation of human lymphocytes induced by polyclonal T-cell mitogens in a dose-dependent manner. FOM also strongly suppressed mixed lymphocyte reaction and interleukin-2 (IL-2) production by T cells. Moreover, FOM inhibited the expressions of IL-2 receptor (CD25) and transferrin receptor (CD71) on the activated T-cell surfaces. These data suggest that FOM may block the T-cell division during the transition from G1 to S phase of the cell cycle. sheep erythrocytes (E). T cells were obtained by treating E+ cells with lysing buffer (NH4Cl:KHCO3).Reagents. Fosfomycin sodium (1R, 2S-1,2-epoxypropyl phosphonic acid; FOM) and enantiomer of fosfomycin (1S, 2R-1,2-epoxypropyl phosphonic acid) were supplied by Meiji Seika Ltd., Tokyo, Japan. FK506 and Cs-A were donated by Fujisawa Pharmaceutical Co. Ltd. (Osaka, Japan) and Sandoz (Basel, Switzerland), respectively. These drugs were dissolved in ethanol, further diluted in medium, and added to the cultures. Phytohemagglutinin (PHA) and pokeweed mitogen (PWM) were obtained from Difco Laboratories (Detroit, Mich.) and GIBCO Laboratories (Grand Island, N.Y.), respectively. Recombinant human interleukin-2 (IL-2) was donated by Shionogi Pharmaceutical Co. (Osaka, Japan). Fluorescein isothiocyanate-conjugated anti-CD25 monoclonal antibody (IL-2R1) and fluorescein isothiocyanate-conjugated anti-CD71 monoclonal antibody (T9) were purchased from Coulter Immunology (Hialeah, Fla.).Measurement of lymphocyte proliferation. Lymphocytes were cultured in triplicate in 96-well flat-bottomed microplates at 37°C, 5% CO2. The culture medium consisted of RPMI 1640 supplemented with 10% heat-inactivated fetal calf serum, streptomycin (100 ,ug/ml), penicillin (100 U/ml), and 2-mercaptoethanol (0.005 mM

Fosfomycin

“…On the other hand, concentrations of TNF-␣, IL-1␤, and IL-6 expressed as protein and mRNA were almost identical with and without fosfomycin in healthy volunteers (19). Fosfomycin suppresses IL-2 production from T cells (20), the production of leukotriene B4 (LTB4) from neutrophils, and the expression of IL-8 mRNA by LTB4 from monocytes (21). Fosfomycin also exhibits an immunomodulatory effect on B-cell activation (22).…”

Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro

“…T cells were obtained by treating E+ cells with lysing buffer. E-cells were utilized as B-cell sources (12).…”

Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

“…Regarding the adaptive immune system, fosfomycin has been shown to inhibit in vitro the activation of human Band T-lymphocytes [84,85]. Fosfomycin is also thought to decrease the production of proinflammatory cytokines [such as interleukin (IL)-1 , IL-1 , tumour necrosis factor-alpha (TNF ) and IL-8) and increase the production of other cytokines (IL-6 and IL-10) [86,87].…”