Eμ-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction
Eμ-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction
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DOI：
10.1073/pnas.0901166106
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发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Gribben, John G.
中科院分区：
文献类型：
--
作者：
Gorgun, Gullu;Ramsay, Alan G.;Gribben, John G.
临床前动物模型在很大程度上忽略了在人类癌症中重要的免疫抑制机制。这种模型的识别和使用应该能够更好地预测人类对免疫疗法的成功反应。作为癌症诱导非恶性细胞变化的模型，我们在慢性淋巴细胞白血病（CLL）E mu-TCL 1转基因小鼠模型中检测了T细胞功能。随着白血病的发展，E mu-TCL 1转基因小鼠出现了功能性T细胞缺陷以及基因和蛋白质表达的改变，与CLL人类患者中观察到的变化非常相似。此外，将CLL细胞输注到年轻的E mu-TCL 1小鼠中诱导的缺陷与在患有白血病的小鼠中观察到的缺陷相当，表明白血病和T细胞缺陷之间存在因果关系。改变的途径涉及调节肌动蛋白重塑的基因，T细胞表现出免疫突触形成和T细胞信号传导功能障碍，这被免疫调节药物来那度胺逆转。这些结果进一步证明了这种CLL动物模型的实用性，并定义了一种多功能模型来研究癌症诱导的免疫抑制和免疫修复策略的分子机制。
Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) E mu-TCL1 transgenic mouse model. With development of leukemia, E mu-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young E mu-TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.