Banti Shanta, Miller Patrick J, Parker Cynthia D, Ananth Sandya L, Horn LaShun L, Babu Yarlagadda S, Sandhu Jasbir S
Department of Biological Sciences, BioCryst Pharmaceuticals, Inc, Birmingham, AL 35244, USA.
Int Immunopharmacol. 2002 Jun;2(7):913-23. doi: 10.1016/s1567-5769(02)00034-6.
Purine nucleoside phosphorylase (PNP) deficiency in humans produces a relatively selective depletion of T-cells. Inhibitors of PNP are therefore of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP and in vitro T-cell proliferation. Inhibition of human T-cells by BCX-1777 and deoxyguanosine (dGuo) is accompanied by deoxyguanosine triphosphate (dGTP) accumulation. Unlike human T-cells, mouse, rat, dog and monkey T-cells are neither inhibited (IC50>100 microM) nor accumulate dGTP in the presence of BCX-1777 and dGuo. Cells pretreated with BCX-1777 and dGuo for 24 h (to elevate dGTP levels) prior to stimulation demonstrated 80% inhibition similar to the inhibition observed with cells treated with BCX-1777 and dGuo during the stimulation and proliferation process. This further confirms that inhibition of T-cells is due to the accumulation of dGTP in these cells. Deoxynucleotide (dNTP) analysis of the cells treated with BCX-1777 and dGuo for 48 h showed no significant change in deoxycytidine triphosphate (dCTP) and deoxyadenosine triphosphate (dATP) pools. However, a decrease (2-fold) in thymidine triphosphate (dTTP) pools, and a large increase in dGTP pools (15-fold) were observed. Results from various groups have shown that alteration in the dNTP supply results in DNA fragmentation and cell death with characteristics of apoptosis. Indeed, apoptosis is observed in human T-lymphocytes treated with BCX-1777 and dGuo. To compare the in vivo efficacy of BCX-1777 with another potent T-cell inhibitor, cyclosporin, these drugs were tested in a xenogeneic graft-vs.-host disease model (XGVHD). In this model, human lymphocytes are engrafted into severe combined immunodeficient mice (SCID) mice inducing severe XGVHD. The efficacy of BCX-1777 in the XGVHD model was comparable to cyclosporin and a combination of BCX-1777 and cyclosporin treatment showed a trend towards increased efficacy compared to cyclosporin alone. These results suggest that BCX-1777 may be useful for the treatment of disease characterized by activated T-cell responses.
人类嘌呤核苷磷酸化酶（PNP）缺乏会导致T细胞相对选择性耗竭。因此，PNP抑制剂作为潜在的T细胞选择性免疫抑制剂备受关注。BCX-1777是一种有效的PNP抑制剂，可抑制体外T细胞增殖。BCX-1777和脱氧鸟苷（dGuo）对人类T细胞的抑制作用伴随着三磷酸脱氧鸟苷（dGTP）的积累。与人类T细胞不同，在BCX-1777和dGuo存在的情况下，小鼠、大鼠、狗和猴的T细胞既不受抑制（IC50>100 microM），也不积累dGTP。在刺激前用BCX-1777和dGuo预处理24小时（以提高dGTP水平）的细胞，其抑制率为80%，与在刺激和增殖过程中用BCX-1777和dGuo处理的细胞所观察到的抑制率相似。这进一步证实了T细胞的抑制是由于这些细胞中dGTP的积累。对用BCX-1777和dGuo处理48小时的细胞进行脱氧核苷酸（dNTP）分析，结果显示三磷酸脱氧胞苷（dCTP）和三磷酸脱氧腺苷（dATP）池没有显著变化。然而，观察到三磷酸胸腺嘧啶核苷（dTTP）池减少（2倍），而dGTP池大幅增加（15倍）。不同研究组的结果表明，dNTP供应的改变会导致DNA片段化和具有凋亡特征的细胞死亡。事实上，在用BCX-1777和dGuo处理的人类T淋巴细胞中观察到了凋亡。为了比较BCX-1777与另一种有效的T细胞抑制剂环孢素在体内的疗效，在异种移植物抗宿主病模型（XGVHD）中对这些药物进行了测试。在该模型中，将人类淋巴细胞移植到严重联合免疫缺陷小鼠（SCID）体内，诱发严重的XGVHD。BCX-1777在XGVHD模型中的疗效与环孢素相当，与单独使用环孢素相比，BCX-1777和环孢素联合治疗显示出疗效增加的趋势。这些结果表明，BCX-1777可能对治疗以活化T细胞反应为特征的疾病有用。
Zotero 插件