CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack
CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack
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DOI：
10.1111/j.1365-2141.2004.05225.x
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发表时间：
2004-11-01
影响因子：
6.5
通讯作者：
Eldering, E
中科院分区：
文献类型：
--
作者：
Kater, AP;Evers, LM;Eldering, E
为了提高b细胞慢性淋巴细胞白血病（B-CLL）较差的抗原呈递能力，CD40触发被认为是一种主动免疫疗法。然而，CD40刺激也具有抗凋亡作用，并可能进一步损害B-CLL对凋亡刺激的失调反应。因此，我们在CD40刺激前后测量了几乎所有凋亡调节因子的表达。这些发现与化疗和死亡受体诱导的细胞凋亡和t细胞介导的杀伤的敏感性相关。CD40刺激通过上调Bcl-xL和bcl -1，下调BH3-only蛋白Harakiri，增强了B-CLL细胞的组成性抗凋亡谱。出乎意料的是，BH3-only蛋白Bid被强烈诱导。在功能上，cd40刺激的B-CLL细胞对药物诱导的凋亡产生了抗性，尽管CD95和Bid上调，但对CD95L不敏感。相比之下，在CD40刺激之前和之后，通过装载病毒（CMV）肽触发的自体T细胞杀伤都非常有效。在CTL相互作用下，CLL靶标发生线粒体去极化和caspase-3激活。因此，尽管抗凋亡谱增强，CD40触发的B-CLL细胞仍然是常驻细胞毒性T细胞的极佳靶点。这些数据支持在B-CLL中利用CD40刺激进行治疗，前提是诱导了强CTL成分。
To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy. However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli. Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation. These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing. CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri. Unexpectedly, the BH3-only protein Bid was strongly induced. Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation. Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation. Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells. These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induced.