Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells: A model for immunotherapy
Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells: A model for immunotherapy
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DOI：
10.1016/s0301-472x(01)00668-3
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发表时间：
2001-08-01
影响因子：
2.6
通讯作者：
Brenner, M
中科院分区：
文献类型：
--
作者：
Dotti, G;Savoldo, B;Brenner, M
Objective. CD 40 L恢复某些B细胞肿瘤的抗原呈递细胞（APC）功能，并诱导专职APC成熟。因此，我们评估了转基因CD 40 L表达对人多发性骨髓瘤（MM）细胞的行为和免疫原性的影响。通过腺病毒载体基因转移，在CD 40（+）（RPMI 8226）和CD 40（-）（U266 B1）人骨髓瘤细胞系（HMCL）中诱导CD 40 L表达。通过每日台盼蓝染色和甲基-H-3-胸苷掺入测定对照HMCL和HMCL/CD 40 L的活力和增殖活性。采用同种异体单个核细胞（MNCs）混合淋巴细胞反应（MLR）和同种异体树突状细胞（DCs）与表达转基因CD 40 L的HMCL共培养的方法，评价修饰的HMCL的APC功能以及旁观者DCs在诱导抗肿瘤免疫应答中的作用。CD 40 L表达可显著抑制CD 40（+）HMCL的生长，并诱导其凋亡。对于CD 40- HMCL，这些影响不太明显。在CD 40 L表达后，HMCL上的共刺激分子没有上调。两种表达转基因CD 40 L的HMCL均诱导旁观者DC成熟，并增强其刺激MNCs增殖的能力。用表达CD 40 L的免疫原性差的RPMI 8226培养的DC上调了IFN-γ和其他Th 1细胞因子（白细胞介素-2、肿瘤坏死因子-α）的T淋巴细胞释放。我们的数据表明，CD 40 L的转基因表达具有双重作用，有利于产生对人MM的免疫反应。当肿瘤细胞为CD 40（+）时，CD 40 L与肿瘤细胞上的CD 40抗原的接合诱导其细胞凋亡，从而允许肿瘤专业APC吸收相关抗原。不依赖于肿瘤细胞表达CD 40，肿瘤细胞上的CD 40 L转基因表达允许它们刺激CD 40（+）APC，以增加它们的成熟和它们刺激细胞毒性T淋巴细胞（CTL）的能力，所述细胞毒性T淋巴细胞（CTL）识别APC可能吞噬的肿瘤衍生抗原。(C)2001年国际实验血液学学会。出版社：Elsevier Science
Objective. CD40L restores the antigen-presenting cell (APC) function of some B-cell tumors and induces professional APC maturation. We therefore evaluated the effects of transgenic CD40L expression on the behavior and immunogenicity of human multiple myeloma (MM) cells.Materials and Methods. CD40L expression was induced in a CD40(+) (RPMI 8226) and a CD40(-) (U266B1) human myeloma cell line (HMCL) by adenoviral vector gene transfer. The viability and proliferative activity of control HMCL and HMCL/CD40L were determined by daily trypan blue staining and methyl-H-3-thymidine incorporation. Mixed lymphocyte reaction (MLR) with allogeneic mononuclear cells (MNCs) and coculture of allogeneic dendritic cells (DCs) with HMCL expressing transgenic CD40L were used to evaluate the APC function of modified HMCL as well as the role of bystander DCs in inducing an anti-tumor immune response.Results. CD40L expression significantly inhibited the growth of the CD40(+) HMCL and induced apoptosis. These effects were less evident for the CD40- HMCL. There was no upregulation of costimulatory molecules on either HMCL following CD40L expression. Both HMCL expressing transgenic CD40L induced maturation of bystander DCs and enhanced their ability to stimulate the proliferation of MNCs. DCs cultured with the poorly immunogenic RPMI 8226 expressing CD40L upregulated T-lymphocyte release of IFN-gamma and other Th1 cytokines (interleukin-2, tumor necrosis factor-alpha).Conclusions. Our data suggest that transgenic expression of CD40L exerts a dual effect favoring generation of an immune response to human MM. Where the tumor cells are CD40(+), the engagement of CD40 antigen by CD40L on tumor cells induces their apoptosis, allowing uptake of tumor-associated antigen by professional APC. Independently of tumor-cell expression of CD40, transgenic expression of CD40L on tumor cells allows them to stimulate CD40(+) APC, to increase their maturation and their capacity to stimulate cytotoxic T lymphocytes (CTL) that recognize the tumor-derived antigens the APC may have engulfed. (C) 2001 International Society for Experimental Hematology. Published by Elsevier Science.