Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells
Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells
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DOI：
10.1002/art.23447
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发表时间：
2008-05-01
影响因子：
--
通讯作者：
Harada, Mine
中科院分区：
文献类型：
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作者：
Mitoma, Hiroki;Horiuchi, Takahiko;Harada, Mine
Objective.三种抗肿瘤坏死因子α（anti-TNF α）药物已被证明对类风湿性关节炎（RA）和其他炎症性疾病有效。英夫利西单抗和阿达木单抗已被生产为抗TNF α单克隆抗体，而依那西普是从人II型TNF受体工程。尽管所有3种药物对RA的疗效相同，但英夫利西单抗和阿达木单抗对其他疾病如克罗恩病和韦格纳肉芽肿有效，而依那西普则无效。我们进行了这项研究，以了解不同的临床效果，这些抗肿瘤坏死因子α药物通过分析其生物活性的跨膜TNF α。将稳定表达不可切割形式的跨膜TNF α的Jurkat T细胞用于以下研究：1）抗TNF剂与细胞表面跨膜TNF α的结合活性的流式细胞术分析，2）补体依赖性细胞毒性（CDC），3）通过使用外周血单核细胞的抗体依赖性细胞介导的细胞毒性（ADCC），（4）通过流式细胞术检测细胞凋亡和细胞周期，评估跨膜TNF α的由外向内（反向）信号转导。所有抗TNF α药物均与跨膜TNF α结合。英夫利西单抗和阿达木单抗的CDC活性几乎相等，而依那西普的活性明显较低。3种药物的ADCC活性几乎相等。阿达木单抗和英夫利西单抗诱导跨膜TNF α表达的Jurkat T细胞凋亡和细胞周期阻滞，反映了通过跨膜TNF α的由外向内的信号转导。三种不同的抗TNF药物对跨膜TNF α表现出不同的生物学效应。这一发现表明，抗TNF α抗体的CDC和由外向内信号可能解释了阿达木单抗和英夫利西单抗在克罗恩病和韦格纳肉芽肿病中的成功临床疗效。
Objective. Three anti-tumor necrosis factor alpha (anti-TNF alpha) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNF alpha monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti-TNF alpha agents by analyzing their biologic activities on transmembrane TNF alpha.Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNF alpha were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNF alpha, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mono-nuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNF alpha estimated by apoptosis and cell cycle analysis using flow cytometry.Results. All of the anti-TNF alpha agents bound to transmembrane TNF alpha. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNF alpha-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNF alpha.Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNF alpha. This finding suggests that CDC and outside-to-inside signals by anti-TNF alpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.