IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes
IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes
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DOI：
10.1182/blood-2008-05-156059
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发表时间：
2009-01-29
期刊：
影响因子：
20.3
通讯作者：
Bonini, Chiara
中科院分区：
文献类型：
--
作者：
Kaneko, Shin;Mastaglio, Sara;Bonini, Chiara
同种异体造血干细胞移植后白血病的长期临床缓解依赖于能够自我更新并分化为抗白血病效应器的同种反应性记忆T细胞。这被移植物抗宿主病（GVHD）所抵消。诱导供体T细胞选择性自杀是目前消除GVHD的一种基因治疗方法。不幸的是，基因改造降低了淋巴细胞的同种异体反应性。这与基因修饰淋巴细胞的效应记忆（T-EM）表型有关，并可能限制抗白血病作用。我们假设基因修饰淋巴细胞的同种异体反应性与中枢记忆（T-CM）表型分离。为此，我们在CD28共刺激和IL-2、IL-7或IL-7和IL-15联合培养后，用逆转录病毒载体生成自杀基因修饰的T-CM淋巴细胞。在体外，自杀基因修饰的T-CM细胞在同种异体抗原刺激下自我更新并抵抗激活诱导的细胞死亡。在人源化小鼠模型中，只有用IL-7和IL-15培养的自杀基因修饰的T细胞持续存在，在T- em细胞中分化，并且在引起GVHD方面与未处理的淋巴细胞一样有效。GVHD是通过激活自杀基因机制而停止的。这些结果证明了使用IL-7和IL-15培养的自杀基因修饰的T-CM细胞可以安全利用对抗癌症的同种反应性反应。(血。2009;113:1006 - 1015)
Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (T-EM) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (T-CM) phenotype. To this, we generated suicide gene-modified T-CM lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene-modified T-CM cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene -modified T cells cultured with IL-7 and IL-15 persisted, differentiated in T-EM cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene modified T-CM cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer. (Blood. 2009;113:1006-1015)