苯并噻唑衍生物BD759抗T细胞增殖的机制研究  

Suppressive Effect of a Novel Benzothiazole Derivative BD759 on T Cell Proliferation

作　　者：罗兴燕[1] 邹强[1] 孙海[1] 胡松[1] 唐信威[1] 何莉[2] 夏超亚 王茂田[2] 刘阳[1] 赖翼[2] 

机构地区：[1]成都医学院科研实验中心,成都610500 [2]成都医学院检验医学院,成都610500

出　　处：《中国药学杂志》2015年第15期1313-1318,共6页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资助项目(81273530;81302786);四川省高校科研创新团队(13TD0028);四川省教育厅科研项目(15ZB0233;15ZB0235)

摘　　要：目的探讨新型苯并噻唑衍生物BD759抑制T细胞增殖的作用机制。方法流式细胞术检测T细胞增殖、CD25表达及细胞周期。酶联免疫吸附法测定BD759对活化T细胞分泌白细胞介素-2、白细胞介素-4、白细胞介素-6、白细胞介素-10、白细胞介素-17A及干扰素-γ等细胞因子的影响。结果 BD759抑制抗人CD3和CD28m Abs刺激的T细胞增和混合淋巴细胞反应,IC50分别为(3.5±0.7)和(3.3±0.9)μmol·L-1。BD759对人静息T细胞和外周血单个核细胞无细胞毒性。BD759不抑制活化的T细胞表达CD25和分泌细胞因子白细胞介素-2、白细胞介素-4及白细胞介素-10,但显著抑制白细胞介素-6、白细胞介素-17A和干扰素-γ的产生,并且阻滞细胞周期于G0/G1期。结论新型苯并噻唑衍生物BD759不影响T细胞的活化,但通过阻滞细胞周期于G0/G1期抑制活化的T细胞增殖,并抑制白细胞介素-6、白细胞介素-17A和干扰素-γ等促炎细胞因子的分泌。BD759有望作为先导化合物,开发用于自身免疫性疾病与器官移植的新型药物。OBJECTIVE To determine the immunosuppressive activity of a novel benzothiazole derivative BD759 on T cell prolifration and its potential mode of action. METHODS T cell proliferation, CD25 expression and cell cycle distribution were measured by flow eytometer. Cytokine levels, including IL-2, IL-4, IL-6, IL-10, IL-17A and IFN-γ, were determined by ELISA. RESULTS BD759 significantly inhibited human T cell proliferation, stimulated either by anti-CD3/anti-CD28 monoelonal antibodies or by an al- loantigen, in a dose-dependent manner with IC50 values of （3.5 ±0. 7 ） and （3.3±0. 9 ） μmol· L-1, respectively. No obvious cyto- toxic effects of BD759 were observed on human resting naingve T ceils and peripheral blood mononuelear cells in our experimental condi- tions. Furthermore, BD759 did not inhibit CD25 expression or IL-2, IL-4 and IL-10 secretion, but inhibited IL-6, IL-17A and IFN-γ production and induced cell cycle arrest at the G0/G1 phase in activated T cells. CONCLUSION These data indicate that BD759 has no effect on T cell activation, but induces T cell cycling arrest at G0/G1 phase. BD759 also inhibits the secretion of inflammatory eyto- kines, such as IL-6, IL-17A and IFN-gamma. Thus, BD759 has the potential to be used as a lead compound for the design and development of new immunosuppressants for treating autoimmune diseases and preventing graft rejection.

关 键 词：苯并噻唑衍生物 T细胞增殖 免疫抑制剂 细胞周期 

分 类 号：R967[医药卫生—药理学]