CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells
CTLA-4 is not restricted to the lymphoid cell lineage and can function as a target molecule for apoptosis induction of leukemic cells
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DOI：
10.1182/blood-2002-06-1668
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发表时间：
2003-01-01
期刊：
影响因子：
20.3
通讯作者：
Ferrara, GB
中科院分区：
文献类型：
--
作者：
Pistillo, MP;Tazzari, PL;Ferrara, GB
研究了细胞毒性t淋巴细胞抗原-4 （CTLA-4）分子在人正常和肿瘤造血细胞中细胞膜和细胞间室的表达。用一组抗CTLA-4人可变结构域单链片段（scFv）抗体进行的流式细胞术分析显示，CTLA-4在表面不表达，而在细胞质中，在新分离的外周血单核细胞（PBMCs）、T细胞、B细胞、CD34（+）干细胞和粒细胞中高度表达。使用能够特异性激活每种细胞类型的药剂进行各种处理可诱导这些细胞表面的CTLA-4表达。同样，在不同的造血细胞系中也观察到CTLA-4的表达增加，尽管它们在激活前也表达了不同程度强度的表面CTLA-4。令人惊讶的是，CTLA-4 RNA转录物仅在CTLA-4细胞外结构域的巢式聚合酶链反应（PCR）后才能在这些细胞系中检测到，这表明CTLA-4 RNA的快速加工伴随着CTLA-4蛋白的长时间积累。我们进一步证实了CTLA-4在多种急性和慢性髓系白血病（aml和cml）以及B淋巴和t淋巴细胞白血病中的表面表达，无论是成人还是儿童。CTLA-4在25% - 85%的aml和cml中表达，这取决于白血病亚型和所分析的表位，而在急性t型白血病中，CTLA-4主要在细胞质中表达。慢性B型白血病在细胞表面和细胞质中均表达CTLA-4，而慢性T型白血病很少呈阴性。两种抗CTLA-4免疫毒素（scFvs-saporin）诱导典型AML肿瘤细胞体外凋亡，提示基于CTLA-4靶向的AML免疫治疗新途径。(C) 2003年由美国血液病学会出版。
The expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4) molecule in human normal and neoplastic hematopoietic cells, both on the cell membrane and in the intracellular compartment, was evaluated. Flow cytometric analysis carried out with a panel of anti-CTLA-4 human single-chain fragment of variable domain (scFv) antibodies revealed that CTLA-4 was not expressed on the surface, whereas it was highly expressed within the cytoplasm, In freshly isolated peripheral blood mononuclear cells (PBMCs), T cells, B cells, CD34(+) stem cells, and granulocytes. Various treatments with agents able to specifically activate each cell type induced CTLA-4 expression on the surface of these cells. Similarly, increased CTLA-4 expression was observed in different hematopoietic cell lines although they also expressed surface CTLA-4, at different degrees of intensity, before activation. Surprisingly, CTLA-4 RNA transcripts were detectable in such cell lines only after nested polymerase chain reaction (PCR) specific for CTLA-4 extracellular domain, suggesting a very fast CTLA-4 RNA processing accompanied by prolonged CTLA-4 protein accumulation. We further demonstrated surface expression of CTLA-4 in a variety of acute and chronic myeloid leukemias (AMLs and CMLs) and B- and T-lymphoid leukemias, either adult or pediatric. CTLA-4 was expressed in 25% to 85% of AMLs and CMLs depending on the leukemia subtype and the epitope analyzed, whereas in acute Band T-leukemias CTLA-4 expression was mainly cytoplasmic. Chronic B leukemias appeared to express CTLA-4, both on the surface and in cytoplasm, whereas few cases tested of chronic T leukemias were negative. Two anti-CTLA-4 immunotoxins (scFvs-saporin) induced in vitro apoptosis of neoplastic cells from a representative AML, suggesting a novel immunotherapeutic approach to AML based on CTLA-4 targeting. (C) 2003 by The American Society of Hematology.