Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany.
Clin Exp Immunol. 2013 Aug;173(2):288-97. doi: 10.1111/cei.12109.
2-Chlorodeoxyadenosine (cladribine, CdA) is an immunosuppressive drug that is licensed to treat hairy cell leukaemia, and has been shown recently to have beneficial effects in patients with multiple sclerosis (MS). The therapeutic effects of CdA have been suggested to be mediated partly through its potent toxicity towards lymphocytes. However, the effects of CdA on other immune cells are poorly understood. In the present study, we investigated the effects of CdA on the induction of apoptosis in human monocytes, monocyte-derived immature (ImDC) and mature (mDC) dendritic cells. Treatment of monocytes with CdA strongly induced apoptosis after 24 h, while apoptosis induction in DC was evident after 72 h. Furthermore, CdA treatment strongly induced caspase-3 and caspase-9 in monocytes, whereas activation of caspases was undetected in DC. The mitochondrial membrane potential in DC was reduced significantly after CdA treatment. DNA hypodiploid assessment showed fragmented nuclei in DC after CdA treatment together with activation of p53 protein. These results revealed that CdA induces caspase-independent apoptosis in DC and suggest cell type specific effects of CdA. This mechanism may contribute to the effect of CdA in autoimmune diseases.
2-氯脱氧腺苷（克拉屈滨，CdA）是一种免疫抑制剂，已获许可用于治疗毛细胞白血病，最近有研究表明它对多发性硬化症（MS）患者有益。CdA 的治疗效果部分是通过其对淋巴细胞的强烈毒性介导的。然而，CdA 对其他免疫细胞的影响尚不清楚。在本研究中，我们研究了 CdA 对人单核细胞、单核细胞衍生的未成熟（ImDC）和成熟（mDC）树突状细胞凋亡诱导的影响。单核细胞用 CdA 处理 24 小时后强烈诱导凋亡，而 DC 中的凋亡诱导在 72 小时后明显。此外，CdA 处理强烈诱导单核细胞中的 caspase-3 和 caspase-9，而 DC 中未检测到 caspase 的激活。CdA 处理后，DC 中的线粒体膜电位显著降低。DNA 亚二倍体评估显示 CdA 处理后 DC 中有核碎片，并激活 p53 蛋白。这些结果表明 CdA 诱导 DC 中的 caspase 非依赖性凋亡，并提示 CdA 具有细胞类型特异性作用。这种机制可能有助于 CdA 在自身免疫性疾病中的作用。
