The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo:: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders
The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo:: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders
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DOI：
10.1073/pnas.080068597
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发表时间：
2000-04-11
影响因子：
11.1
通讯作者：
Wasik, MA
中科院分区：
文献类型：
--
作者：
Majewski, M;Korecka, M;Wasik, MA
而标准的免疫抑制剂促进移植后淋巴组织增生性疾病（PTLD）的发展，RAD，一种具有强效免疫抑制特性的大环内酯类药物，和其他免疫抑制大环内酯类药物对这些疾病的影响仍不确定。我们发现RAD对六种不同PTLD样EB病毒+淋巴母细胞样B细胞系的体外生长具有深刻的抑制作用。与正常T细胞相似，RAD在PTLD样B细胞中阻断细胞周期进展的早期（G（0）/G（1））期。此外，RAD增加了这些细胞的凋亡率。该药物还对皮下异种移植的PTLD样EB病毒+ B细胞的生长具有显著的抑制作用。SCID小鼠RAD效应的程度在所测试的三种B细胞系之间变化，并且与其在体外对细胞系的效应成比例。在该体内异种移植模型中，RAD显著延迟了已建立的肿瘤的生长或诱导其消退。在一条线上，它能够根除八只小鼠中的四只小鼠的肿瘤。当RAD处理在肿瘤细胞注射之前开始时，在所有三个系中观察到肿瘤生长的显著抑制。在其中两个实验中，该药物阻止了大约50%的小鼠（5/11和5/8）的肿瘤建立。总之，RAD是体外和体内PTLD样细胞的有效抑制剂。这些发现表明，与标准免疫抑制剂相比，大环内酯类药物如RAD可能有效预防和治疗PTLD。
Whereas the standard immunosuppressive agents foster development of posttransplant lymphoproliferative disorders (PTLDs), the impact of RAD, a macrolide with potent immunosuppressive properties, and other immunosuppressive macrolides on these disorders remains undetermined. We found that RAD had a profound inhibitory effect on in vitro growth of six different PTLD-like Epstein-Barr virus+ lymphoblastoid B cell lines. Similar to normal Tcells, RAD blocked cell-cycle progression in PTLD-like B cells in the early (G(0)/G(1)) phase. Furthermore, RAD increased the apoptotic rate in such cells. The drug also had a profound inhibitory effect on the growth of PTLD-like Epstein-Barr virus+ B cells xenotransplanted s.c. into SCID mice. The degree of the RAD effect varied among the three B cell lines tested and was proportional to its effects on the cell lines in vitro. In this in vivo xenotransplant model, RAD markedly delayed growth or induced regression of the established tumors. In one line, it was able to eradicate the tumor in four of eight mice. When RAD treatment was initiated before tumor cell injection, a marked inhibition of tumor growth was seen in all three lines. In two of them, the drug prevented tumor establishment in approximately 50% of mice (5/11 and 5/8). In summary, RAD is a potent inhibitor of PTLD-like cells in vitro and in vivo. These findings indicate that, in contrast to the standard immunosuppressive agents, macrolides such as RAD may be effective in prevention and treatment of PTLDs.