Safety and efficacy of activated transfected killer cells for neutropenic fungal infections.
Safety and efficacy of activated transfected killer cells for neutropenic fungal infections.
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激活的转染杀伤细胞治疗中性粒细胞减少性真菌感染的安全性和有效性。
DOI：
10.1086/652496
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Spellberg,Brad
中科院分区：
文献类型：
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作者：
Lin,Lin;Ibrahim,AshrafS;Baquir,Beverlie;Fu,Yue;Applebaum,David;Schwartz,Julie;Wang,Amy;Avanesian,Valentina;Spellberg,Brad
背景：侵袭性真菌感染导致中性粒细胞减少症患者相当高的发病率和死亡率。白细胞输注是治疗此类感染的一种有前途的治疗方法，但技术障碍阻碍了其广泛使用。方法。为了概括白细胞输注，我们正在开发一种使用吞噬细胞系 HL-60 的基于细胞的免疫疗法。我们试图用自杀陷阱（单纯疱疹病毒胸苷激酶）稳定转染 HL-60 细胞，以便在需要时清除细胞，并使用生物发光标记来跟踪小鼠体内的细胞。结果。尽管在液氮中连续培养或储存 20 个月，转染仍然稳定。用视黄酸和二甲磺胺甲恶唑激活这些转染细胞增强了它们的杀菌效果。暴露于更昔洛韦后，激活的转染杀伤细胞（ATAK）被完全消除，证实了自杀陷阱的功能。 ATAK细胞改善了患有致命性播散性念珠菌病和吸入性曲霉病的中性粒细胞减少小鼠的存活率。生物发光和组织病理学分析证实，在更昔洛韦治疗后，存活小鼠的细胞被清除。综合尸检、组织病理学和代谢组学分析显示细胞没有毒性。结论。这些结果为继续转化开发这种用于治疗中性粒细胞减少宿主难治性感染的有前途的新技术奠定了基础。
Background.Invasive fungal infections cause considerable morbidity and mortality in neutropenic patients. White blood cell transfusions are a promising treatment for such infections, but technical barriers have prevented their widespread use.Methods.To recapitulate white blood cell transfusions, we are developing a cell-based immunotherapy using a phagocytic cell line, HL-60. We sought to stably transfect HL-60 cells with a suicide trap (herpes simplex virus thymidine kinase), to enable purging of the cells when desired, and a bioluminescence marker, to track the cells in vivo in mice.Results.Transfection was stable despite 20 months of continuous culture or storage in liquid nitrogen. Activation of these transfected cells with retinoic acid and dimethyl sulfamethoxazole enhanced their microbicidal effects. Activated transfected killer (ATAK) cells were completely eliminated after exposure to ganciclovir, confirming function of the suicide trap. ATAK cells improved the survival of neutropenic mice with lethal disseminated candidiasis and inhalational aspergillosis. Bioluminescence and histopathologic analysis confirmed that the cells were purged from surviving mice after ganciclovir treatment. Comprehensive necropsy, histopathology, and metabolomic analysis revealed no toxicity of the cells.Conclusions.These results lay the groundwork for continued translational development of this promising, novel technology for the treatment of refractory infections in neutropenic hosts.