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.

The effect of pravastatin on acute rejection after kidney transplantation--a pilot study.

Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 +/- 9.3 vs. 236.5 +/- 11.9 mg/dl, P < 0.02), LDL levels (107.9 +/- 6.6 vs.149.6 +/- 10.7 mg/dl, P < 0.002), and triglyceride levels (118.8 +/- 14.2 vs. 157.2 +/- 13.8 mg/dl, P < 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%, P = 0.01), the incidence of multiple rejections episodes (P < 0.05), and the use of both pulse methylprednisolone (P = 0.01) and OKT3 (P = 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 +/- 1.6 vs. 20.0 +/- 2.0% lysis of K562 target cells, P < 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression.

[Tube pregnancy treated with trichosanthin and followed up by hysterosalpingography].

Twenty cases of unruptured tube pregnancy were treated with Trichosanthin intramuscularly given. Only two cases were eventually operated, so the effective rate was 90%. The hysterosalpingography was taken in 14 of 18 cases who was willing to accept the procedure at 0.5-1.5 year after the conservative treatment. Both tubes were patent in 10 of 14 cases, the rate of patency was 71.4%.

A new microcellular cytotoxicity test based on calcein AM release.

We present a microtest for cell-mediated immunity, based on the use of the Tarasaki tray and calcein AM vital dye. The number of target cells needed has been reduced to 500 per test with a corresponding tenfold reduction in the number of effector cells needed. Results were read at the rate of 1 second per test using a fluorimeter attached to a microscope. Each reaction was also confirmed visually with the use of ethidium bromide as a counterstain for dead cells. The calcein AM dye used to stain the living cells was shown to have a low spontaneous leakage rate--less than 15% in 4 hours at 37 degrees C. Dilutions of targets stained by calcein AM had a linear relationship with measured fluorescence values. NK cells, LAKs, and CTLs were readily detectable by this microtest. Quantitation of killing and kinetic analysis was readily performed with this test system. A significant positive correlation to 51Cr-release results was found. We conclude that the microtest should find wide application in studies of cell-mediated immunity.

[Clinical study of termination of early pregnancy by combination of dl-15-methyl-prostaglandin F2 alpha and RU 486].

PIP: In order to study the appropriate dosage in using RU 486 for induced abortion, 80 women of or = 49 days of pregnancy were randomly assigned to 3 groups. 20 women in Group I took 175 mg of RU486 in 3 1/2 days and were given 1 mg injection of prostaglandin (PG) on the 4th day. 20 women in Group II took the same amount of RU486 as group I and were given 0.5 mg of PG injection on the 4th day. 40 women in Group III took 100 mg of RU486 in 2 days and were given 0.5 mg of PG on the 3rd day. The duration of induced abortion and bleeding and the side effects were observed. The outcome of induced abortion was classified as complete abortion, incomplete abortion, and failure. No failures occurred. About 95% of the women in each group had a complete abortion, and the differences among the 3 groups were not statistically significant. Those who had an incomplete abortion received a medical abortion. A small number of women experienced the side effects of dizziness, nausea, vomiting, and diarrhea. Compared with studies with a similar proportion of complete abortion, the dosage of RU486 in this study is 2-4 times smaller, and the dosage of PG is also reduced by 5 to 14 times that used in earlier studies. Signs of incomplete abortion should be closely observed, and action should be taken to avoid excessive bleeding or infection. Drug-induced abortion is gradually gaining acceptance; nevertheless, appropriate medical attention is necessary to guard against complications.^ieng

Pathogenetic role of anti-vascular endothelial cell antibodies in systemic lupus erythematosus.

In order to study the relationship between vascular endothelial cell (VEC) antigen system and systemic lupus erythematosus (SLE), including lupus nephritis, Terasaki's microcytotoxicity test and indirect immunofluorescence were used to detect anti-VEC antibody. VEC was identified by electron microscopy. Sera of 21 SLE patients and of 100 healthy donors were examined. Among the 21 SLE patients evaluated, 17 had kidney injury and 13 were in active stage SLE. Results showed that anti-VEC antibody was found in 76.2% of 21 SLE patients, while only 1% of the controls were positive (P less than 0.05). This antibody was detected in 84.6% of patients in active stage SLE and in 62.5% of patients in inactive stage (P greater than 0.05). In patients with and without kidney injury, it was detected in 82.4% and 50%, respectively (P greater than 0.05). These data show that anti-VEC antibody does exist in the sera of SLE patients, the presence of which is closely related to SLE onset and is independent of whether the patient is in active stage of SLE or has kidney injury. In summary, our data suggest that anti-VEC antibody may be one of the triggering factors in the vasculitis of SLE. It is proposed that renal VEC may act as a target cell which can be attacked by anti-VEC antibody to constitute an in-situ immune complex formation in the kidney, leading to lupus nephritis.

Detection of anti-vascular endothelial cell antibodies with microcytotoxicity testing.

Antivascular endothelial cell antibodies (anti-VEC) were detected in 20 out of 20 serum samples from post renal transplant nephrectomy patients using a microcytotoxicity (MET) test, but in only 1 of 100 healthy blood donors. Cytotoxicity to VEC could occur in the absence of lymphocytotoxic antibodies. In this paper factors influencing the specificity and sensitivity of microcytotoxicity on vascular endothelial cell (VEC) were studied, including improvements in the preparation of VEC from an umbilical cord vein to get 95% and more of purity and viability; adequate dilution of rabbit sera to reduce its nonspecific VEC cytotoxic effect; and results read by exactly adjusted phase contrast microscopy to reduce the percentage of false negative. The original titers of allotypic and monoclonal antibodies against VEC have been shown to be reproducible in repeated testing during the past two years. The recognition of the weak cytotoxic effects of anti-HLA on VEC makes possible direct application of microcytotoxicity on VEC, to detect anti-VEC and to study VEC antigen classification (through a comparison of the cytotoxic effects of tested sera on VEC and concordant lymphocytes).