THE INHIBITORY EFFECTS OF PRAVASTATIN ON NATURAL-KILLER-CELL ACTIVITYIN-VIVO AND ON CYTOTOXIC T-LYMPHOCYTE ACTIVITY IN-VITRO

Background: We have reported that heart transplant recipients treated with pravastatin demonstrate decreases in the incidence of clinically severe acute rejection episodes, the incidence and progression of tran splant coronary vasculopathy, and natural killer cytotoxicity. These p atients also exhibited a significant improvement in 1-year allograft s urvival. Because of these clinical findings suggesting an immunosuppre ssive effect of pravastatin unique to transplant recipients and the un clear role of natural killer cells in allograft rejection, we postulat ed that pravastatin may exert its immunomodulatory effect by acting wi th cyclosporine to alter T lymphocyte function. Methods: Twenty patien ts randomized into an ongoing trial of pravastatin after heart transpl antation were monitored serially for natural killer cell cytotoxicity. In a separate experiment, lymphocytes isolated from normal volunteers were treated with various combinations of pravastatin and cyclosporin e and tested for cytotoxic T lymphocyte toxicity in a one-way misted l ymphocyte reaction. Results: Pravastatin-treated heart transplant reci pients exhibited a decrease in natural killer cell cytotoxicity (9.8% mean natural killer cell cytotoxicity vs 22.1% in the control group, p < 0.01). In the one-way mixed lymphocyte reaction with blood obtained from control subjects, there was a synergistic inhibition of cytotoxi c T lymphocyte activity when the cells were cultured in a combination of pravastatin and cyclosporine (20.3% mean cytotoxicity of target cel ls vs 41.4% in the control group, p < 0.01). Conclusions: Pravastatin exerts an immunosuppressive effect in heart transplant recipients as e xpressed by a reduction in rejection and natural killer cell cytotoxic ity. Pravastatin and cyclosporine act synergistically to reduce cytoto xic T lymphocyte activity. This synergistic effect of pravastatin and cyclosporine may explain why this immunosuppressive effect is unique t o transplant recipients.