The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism
The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism
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DOI：
10.1182/blood.v99.4.1314
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发表时间：
2002-02-15
期刊：
影响因子：
20.3
通讯作者：
Jurlander, J
中科院分区：
文献类型：
--
作者：
Pedersen, IM;Buhl, AM;Jurlander, J
抗CD 20抗体可激活补体并在B淋巴细胞中诱导抗体依赖性细胞毒性（ADCC）。在B细胞系中，此类抗体也诱导细胞凋亡。本研究对B细胞慢性淋巴细胞白血病（B-CLL）细胞表面CD 20的表达及功能进行了分析。流式细胞术分析表明，B-CLL细胞表达的CD 20的荧光强度明显弱于正常CD 5（+）和CD 5（-）B细胞以及恶性CD 5-低度非霍奇金淋巴瘤细胞。鉴定了来自健康供体的具有与B-CLL细胞相同的CD 5和CD 20表达模式的细胞的小群体，并且证实该群体是T谱系，而不是B谱系。在存在嵌合抗CD 20抗体利妥昔单抗和交联F（ab）（2）片段的情况下，培养新鲜分离的B-CLL细胞导致剂量和时间依赖性的凋亡诱导。细胞凋亡的诱导发生在补体激活和ADCC的影响可以忽略的条件下。利妥昔单抗的交联诱导3种促分裂原活化蛋白（MAP）激酶c-Jun NH 2-末端蛋白激酶、细胞外信号调节激酶和p38的强烈和持续磷酸化。将p38抑制剂SB 203580引入系统中完全阻断了p38下游的信号传导，如MAPKAP K2活性的缺乏所证明的，并且显著降低了抗CD 20诱导的细胞凋亡的程度。这些结果表明，与新鲜分离的B-CLL细胞上的CD 20结合的利妥昔单抗的交联通过依赖于p38 MAP-激酶活化的信号传导途径诱导细胞凋亡。(C)2002年，美国血液学会。
Antibodies against CD20 can activate complement and induce antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In B-cell lines, such antibodies also induce apoptosis. In this study, the expression and function of CD20 on B-cell chronic lymphocytic leukemia (B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that B-CLL cells express CD20 with a fluorescence intensity that is significantly weaker than that of normal CD5(+) and CD5(-) B cells and that of malignant CD5- low-grade non-Hodgkin lymphoma cells. A small population of cells from healthy donors that have an expression pattern of CD5 and CD20 identical to that of B-CLL cells were identified, and this population was confirmed to be of T lineage, not B lineage. Culture of freshly isolated B-CLL cells In the presence of the chimeric anti-CD20 antibody rituximab and a cross-linking F(ab)(2) fragment, resulted in dose- and time-dependent induction of apoptosis. The induction of apoptosis occurred under conditions in which the influence of complement activation and ADCC was negligible. Cross-linking of rituximab induced strong and sustained phosphorylation of the 3 mitogen activated protein (MAP) kinases c-Jun NH2-terminal protein kinase, extracellular signal-regulated kinase, and p38. Introduction of the p38 inhibitor SB203580 Into the system completely blocked signaling downstream of p38, as evidenced by the absence of MAPKAP K2 activity, and significantly reduced the degree of anti-CD20-induced apoptosis. These results demonstrate that cross-linking of rituximab bound to CD20 on freshly Isolated B-CLL cells induces apoptosis through a signaling pathway that Is dependent on p38 MAP-kinase activation. (C) 2002 by The American Society of Hematology.