对肿瘤特异性细胞毒性T淋巴细胞进行基因操作以恢复对白细胞介素-7的反应性。
Genetic manipulation of tumor-specific cytotoxic T lymphocytes to restore responsiveness to IL-7.
作者信息
Vera Juan F, Hoyos Valentina, Savoldo Barbara, Quintarelli Concetta, Giordano Attianese Greta M P, Leen Ann M, Liu Hao, Foster Aaron E, Heslop Helen E, Rooney Cliona M, Brenner Malcolm K, Dotti Gianpietro
机构信息
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Houston, Texas 77030, USA.
出版信息
Mol Ther. 2009 May;17(5):880-8. doi: 10.1038/mt.2009.34. Epub 2009 Mar 3.
Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTLs) can induce objective clinical responses in patients with malignant diseases. The option of providing a proliferative and survival advantage to adoptively transferred CTLs remains a challenge to improve their efficacy. Host lymphodepletion and administration of recombinant interleukin-2 (IL-2) are currently used to improve CTL survival and expansion after adoptive transfer, but these approaches are frequently associated with significant side effects and may increase proliferation of T regulatory cells. IL-7 is a crucial homeostatic cytokine that has been safely administered as a recombinant protein. However, while IL-7 induces robust expansion of naive and memory T lymphocytes, the lack of expression of the IL-7 receptor alpha chain (IL-7Ralpha) by CTLs precludes their response to this cytokine. We found that CTLs can be genetically modified to re-express IL-7Ralpha, and that this manipulation restores the response of these cells to IL-7 without apparent modification of their antigen specificity or dependency, and without changing their response to other common gamma (gammac) chain cytokines. This approach may allow selective expansion of CTLs without the unwanted effects associated with IL-2.
抗原特异性细胞毒性T淋巴细胞(CTL)的过继性转移可在恶性疾病患者中诱导客观的临床反应。为过继性转移的CTL提供增殖和生存优势的选择仍然是提高其疗效的一项挑战。目前采用宿主淋巴细胞清除和重组白细胞介素-2(IL-2)给药来提高过继性转移后CTL的存活和扩增,但这些方法常常伴有显著的副作用,并且可能增加调节性T细胞的增殖。IL-7是一种关键的稳态细胞因子,已作为重组蛋白安全给药。然而,虽然IL-7可诱导幼稚和记忆性T淋巴细胞的强劲扩增,但CTL缺乏IL-7受体α链(IL-7Rα)的表达使其无法对该细胞因子产生反应。我们发现,可对CTL进行基因改造以重新表达IL-7Rα,并且这种操作可恢复这些细胞对IL-7的反应,而不会明显改变其抗原特异性或依赖性,也不会改变它们对其他常见γ(γc)链细胞因子的反应。这种方法可能允许选择性扩增CTL,而不会产生与IL-2相关的不良影响。
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