NOVEL MECHANISMS OF BREQUINAR SODIUM IMMUNOSUPPRESSION ON T-CELL ACTIVATION

被引:17
作者
FORREST, TL
WARE, RE
HOWARD, T
JAFFEE, BD
DENNING, SM
机构
[1] DUKE UNIV,MED CTR,DEPT MED,DIV CARDIOL,DURHAM,NC 27710
[2] DUKE UNIV,MED CTR,DEPT PEDIAT,DIV HEMATOL ONCOL,DURHAM,NC 27710
[3] DUPONT MERCK PHARMACEUT CO,WILMINGTON,DE 19880
关键词
D O I
10.1097/00007890-199410270-00011
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Brequinar sodium (BQR) is a novel immunosuppressive agent that acts by inhibiting the activity of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine biosynthetic pathway. The activity of BQR as an immunosuppressive agent is believed to be inhibition of antigen-induced lymphocyte proliferation through inhibition of DNA and RNA synthesis. BQR, therefore, has a different mechanism of action than cyclosporine and may potentiate the immununosuppressive effects of cyclosporine. In this study, we determined the effect of BQR on peripheral blood mono nuclear cell (PBMC) activation in a series of in vitro culture systems. In these studies, BQR inhibited PHA-stimulated activation in a dose-dependent fashion beginning at 10(-6) M. The immunosuppressive effect of BQR was similar in magnitude to cyclosporine. Proliferation assays suggested an additive immunosuppression by the combination of BQR and cyclosporine. Similar inhibition of CD2-stimulated or CD3-stimulated activation of PBMC was found. The mechanisms of action of BQR were complex. BQR inhibited interleukin 2 protein production in response to mitogen stimulation. Cell surface interleukin 2 receptor expression was inhibited by BQR. BQR inhibited cell cycle progression, preventing progression from G0/G1 into S and G2 + M phases. BQR had no effect on induction of transcripts for the interleukin 2 receptor, but markedly inhibited the production of transcripts for interleukin 2. Thus, our studies indicate that BQR exerts a potent immunosuppression on mitogen-induced PBMC activation through multiple mechanisms. Consequently, BQR may be an effective agent for immuno suppression in organ transplantation or inflammatory diseases.
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页码:920 / 926
页数:7
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