The inhibitory effects of pravastatin on natural killer cell activity in 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 transplant coronary vasculopathy, and natural killer cytotoxicity. These patients also exhibited a significant improvement in 1-year allograft survival. Because of these clinical findings suggesting an immunosuppressive effect of pravastatin unique to transplant recipients and the unclear role of natural killer cells in allograft rejection, we postulated that pravastatin may exert its immunomodulatory effect by acting with cyclosporine to alter T lymphocyte function.


METHODS
Twenty patients randomized into an ongoing trial of pravastatin after heart transplantation 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 cyclosporine and tested for cytotoxic T lymphocyte toxicity in a one-way mixed lymphocyte reaction.


RESULTS
Pravastatin-treated heart transplant recipients 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 cytotoxic T lymphocyte activity when the cells were cultured in a combination of pravastatin and cyclosporine (20.3% mean cytotoxicity of target cells vs 41.4% in the control group, p < 0.01).


CONCLUSIONS
Pravastatin exerts an immunosuppressive effect in heart transplant recipients as expressed by a reduction in rejection and natural killer cell cytotoxicity. Pravastatin and cyclosporine act synergistically to reduce cytotoxic T lymphocyte activity. This synergistic effect of pravastatin and cyclosporine may explain why this immunosuppressive effect is unique to transplant recipients.
Katznelson
S
S
Division of Nephrology, University of California, Davis, School of Medicine, Sacramento, USA.
Wang
X M
XM
Chia
D
D
Ozawa
M
M
Zhong
H P
HP
Hirata
M
M
Terasaki
P I
PI
Kobashigawa
J A
JA
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000517:prevention & control; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015994:Incidence; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017035:Pravastatin / Q000494:pharmacology / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
D000276:Adjuvants, Immunologic; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D002784:Cholesterol; D017035:Pravastatin