Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion.
Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion.
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靶向多个细胞死亡途径可扩展保质期，并保留人和小鼠中性粒细胞的功能进行输血。
DOI：
10.1126/scitranslmed.abb1069
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发表时间：
2021-07-28
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
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作者：
粒细胞输注（GTX）的临床结果由于保存期短和供体中性粒细胞功能受损而处于不利地位。自发性中性粒细胞死亡是异质性的，由多种途径介导。利用机制知识和药理学筛选，我们确定了一种联合治疗，半胱天冬酶-溶酶体膜透化-氧化剂-坏死性凋亡抑制加粒细胞集落刺激因子（CLON-G），通过同时靶向多个细胞死亡途径改变中性粒细胞命运。CLON-G在体外将人和小鼠中性粒细胞的半衰期从小于1天延长至大于5天。CLON-G处理的老化中性粒细胞的形态和功能与新鲜中性粒细胞相当，对关键效应功能（包括吞噬作用、细菌杀伤、趋化性和活性氧产生）无损害。在一个临床相关的小鼠GTX模型中，用储存的CLON-G处理的3天大中性粒细胞输注增强了宿主防御，减轻了感染诱导的组织损伤，并延长了存活期，与用新鲜中性粒细胞输注一样有效。最后，CLON-G处理延长了保存期，并在免疫缺陷小鼠中保持了体外和体内的无菌采集的人GTX产物的功能。因此，CLON-G治疗代表了在输血医学中储存和应用中性粒细胞的有效和适用的临床程序，提供了改善GTX疗效的治疗策略。
Clinical outcomes from granulocyte transfusion (GTX) are disadvantaged by the short shelf life and compromised function of donor neutrophils. Spontaneous neutrophil death is heterogeneous and mediated by multiple pathways. Leveraging mechanistic knowledge and pharmacological screening, we identified a combined treatment, caspases–lysosomal membrane permeabilization–oxidant–necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which altered neutrophil fate by simultaneously targeting multiple cell death pathways. CLON-G prolonged human and mouse neutrophil half-life in vitro from less than 1 day to greater than 5 days. CLON-G–treated aged neutrophils had equivalent morphology and function to fresh neutrophils, with no impairment to critical effector functions including phagocytosis, bacterial killing, chemotaxis, and reactive oxygen species production. Transfusion with stored CLON-G–treated 3-day-old neutrophils enhanced host defenses, alleviated infection-induced tissue damage, and prolonged survival as effectively as transfusion with fresh neutrophils in a clinically relevant murine GTX model of neutropenia-related bacterial pneumonia and systemic candidiasis. Last, CLON-G treatment prolonged the shelf life and preserved the function of apheresis-collected human GTX products both ex vivo and in vivo in immunodeficient mice. Thus, CLON-G treatment represents an effective and applicable clinical procedure for the storage and application of neutrophils in transfusion medicine, providing a therapeutic strategy for improving GTX efficacy.
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影响因子：
20.3
作者：
Monceaux, Valerie;Chiche-Lapierre, Clarisse;Marteyn, Benoit S.
通讯作者：
Marteyn, Benoit S.
影响因子：
20.3
作者：
Li, Yitang;Prasad, Amit;Luo, Hongbo R.
通讯作者：
Luo, Hongbo R.
影响因子：
4.5
作者：
Lane, T A
通讯作者：
Lane, T A
DOI：
10.3324/haematol.12489
发表时间：
2008-07-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Drewniak, Agata;Boelens, Jaap-Jan;Kuijpers, Taco W.
通讯作者：
Kuijpers, Taco W.
影响因子：
2.9
作者：
Leavey, PJ;Thurman, G;Ambruso, DR
通讯作者：
Ambruso, DR