Furman R R, Asgary Z, Mascarenhas J O, Liou H C, Schattner E J
Division of Hematology-Oncology, Department of Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
J Immunol. 2000 Feb 15;164(4):2200-6. doi: 10.4049/jimmunol.164.4.2200.
Chronic lymphocytic leukemia (CLL) is an indolent malignancy of CD5+ B lymphocytes. CLL cells express CD40, a key regulator of B cell proliferation, differentiation, and survival. In nonmalignant B cells, CD40 ligation results in nuclear translocation and activation of NF-kappaB proteins. Based on observations that in some CLL cases, the tumor cells express both CD40 and its ligand, CD154 (CD40 ligand), we proposed a model for CLL pathogenesis due to CD40 ligation within the tumor. To evaluate this issue, we used freshly isolated CLL B cells to examine constitutive and inducible NF-kappaB activity by electrophoretic mobility shift assay. We consistently observed high levels of nuclear NF-kappaB-binding activity in unstimulated CLL B cells relative to that detected in nonmalignant human B cells. In each case examined, CD40 ligation further augmented NF-kappaB activity and prolonged CLL cell survival in vitro. The principle NF-kappaB proteins in stimulated CLL cells appear to be quite similar to those in nonmalignant human B cells and include p50, p65, and c-Rel. In a CD154-positive case, blocking CD154 engagement by mAb to CD154 resulted in inhibition of NF-kappaB activity in the CLL cells. The addition of anti-CD154 mAb resulted in accelerated CLL cell death to a similar degree as was observed in cells exposed to dexamethasone. These data indicate that CD40 engagement has a profound influence on NF-kappaB activity and survival in CLL B cells, and are consistent with a role for CD154-expressing T and B cells in CLL pathogenesis. The data support the development of novel therapies based on blocking the CD154-CD40 interaction in CLL.
慢性淋巴细胞白血病（CLL）是一种CD5 + B淋巴细胞的惰性恶性肿瘤。CLL细胞表达CD40，这是B细胞增殖、分化和存活的关键调节因子。在非恶性B细胞中，CD40连接导致NF-κB蛋白的核转位和激活。基于在一些CLL病例中肿瘤细胞同时表达CD40及其配体CD154（CD40配体）的观察结果，我们提出了一个由于肿瘤内CD40连接导致CLL发病机制的模型。为了评估这个问题，我们使用新鲜分离的CLL B细胞通过电泳迁移率变动分析来检测组成型和诱导型NF-κB活性。相对于在非恶性人类B细胞中检测到的活性，我们持续观察到未刺激的CLL B细胞中核NF-κB结合活性水平较高。在每个检测的病例中，CD40连接进一步增强了NF-κB活性并延长了CLL细胞在体外的存活时间。受刺激的CLL细胞中主要的NF-κB蛋白似乎与非恶性人类B细胞中的非常相似，包括p50、p65和c-Rel。在一个CD154阳性病例中，用抗CD154单克隆抗体阻断CD154结合导致CLL细胞中NF-κB活性受到抑制。添加抗CD154单克隆抗体导致CLL细胞加速死亡，其程度与在暴露于地塞米松的细胞中观察到的相似。这些数据表明CD40结合对CLL B细胞中的NF-κB活性和存活有深远影响，并且与表达CD154的T细胞和B细胞在CLL发病机制中的作用一致。这些数据支持基于阻断CLL中CD154 - CD40相互作用开发新疗法。
