Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells
Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells
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DOI：
10.1016/j.leukres.2009.08.022
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发表时间：
2010-06-01
影响因子：
2.7
通讯作者：
Rao, Jia
中科院分区：
文献类型：
--
作者：
Kachlany, Scott C.;Schwartz, Amy B.;Rao, Jia
口腔细菌 Aggregatibacter actinomycetemcomitans 通过与易感细胞上的淋巴细胞功能抗原 1 (LFA-1) 相互作用，产生一种白细胞毒素 (LtxA)，该毒素对人类和旧世界灵长类动物的白细胞 (WBC) 具有特异性。为了确定 LtxA 是否可以用作治疗 WBC 疾病的治疗剂，我们测试了该毒素的体外和体内抗白血病活性。 LtxA 可杀死人类恶性白细胞系和急性髓系白血病患者的原代白血病细胞，但健康的外周血单核细胞 (PBMC) 对 LtxA 介导的细胞毒性相对具有抵抗力。细胞系上 LFA-1 的水平与 LtxA 的杀伤相关，并且毒素优先杀死表达激活形式的 LFA-1 的细胞。在人类白血病的 SCID 小鼠模型中，LtxA 具有有效的治疗价值，可导致 LtxA 治疗的小鼠长期存活。将 LtxA 静脉输注到恒河猴中会导致输注后早期白细胞计数下降；然而，红细胞、血小板、血红蛋白和血液化学值并未受到影响。因此，LtxA可能是一种有效且安全的治疗血液恶性肿瘤的新型治疗剂。 (C) 2009 Elsevier Ltd. 保留所有权利。
The oral bacterium, Aggregatibacter actinomycetemcomitans, produces a leukotoxin (LtxA) that is specific for white blood cells (WBCs) from humans and Old World primates by interacting with lymphocyte function antigen-1 (LFA-1) on susceptible cells. To determine if LtxA could be used as a therapeutic agent for the treatment of WBC diseases, we tested the in vitro and in vivo anti-leukemia activity of the toxin. LtxA kills human malignant WBC lines and primary leukemia cells from acute myeloid leukemia patients, but healthy peripheral blood mononuclear cells (PBMCs) are relatively resistant to LtxA-mediated cytotoxicity. Levels of LFA-1 on cell lines correlated with killing by LtxA and the toxin preferentially killed cells expressing the activated form of LFA-1. In a SCID mouse model for human leukemia, LtxA had potent therapeutic value resulting in long-term survival in LtxA-treated mice. Intravenous infusion of LtxA into a rhesus macaque resulted in a drop in WBC counts at early times post-infusion; however, red blood cells, platelets, hemoglobin and blood chemistry values remained unaffected. Thus, LtxA may be an effective and safe novel therapeutic agent for the treatment of hematologic malignancies. (C) 2009 Elsevier Ltd. All rights reserved.