Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells

Comparison among infliximab, etanercept, and adalimumab

Hiroki Mitoma, Takahiko Horiuchi, Hiroshi Tsukamoto, Yasuhiro Tamimoto, yasutaka kimoto, Ayumi Uchino, Kentaro To, Shin Ichi Harashima, Nobuaki Hatta, Mine Harada

研究成果: ジャーナルへの寄稿記事

263 引用 (Scopus)

抄録

Objective. Three anti-tumor necrosis factor α (anti-TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFα 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-TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFα, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results. All of the anti-TNFα agents bound to transmembrane TNFα. 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 TNFα-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFα. Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside-to-inside signals by anti-TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

元の言語英語
ページ(範囲)1248-1257
ページ数10
ジャーナルArthritis and Rheumatism
58
発行部数5
DOI
出版物ステータス出版済み - 5 1 2008

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Tumor Necrosis Factor-alpha
Antibody-Dependent Cell Cytotoxicity
Granulomatosis with Polyangiitis
Jurkat Cells
Crohn Disease
Signal Transduction
Rheumatoid Arthritis
Complement C2
Apoptosis
T-Lymphocytes
Tumor Necrosis Factor Receptors
Cell Cycle Checkpoints
Adalimumab
Etanercept
Infliximab
Blood Cells
Cell Cycle
Flow Cytometry
Monoclonal Antibodies
Antibodies

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

これを引用

Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells : Comparison among infliximab, etanercept, and adalimumab. / Mitoma, Hiroki; Horiuchi, Takahiko; Tsukamoto, Hiroshi; Tamimoto, Yasuhiro; kimoto, yasutaka; Uchino, Ayumi; To, Kentaro; Harashima, Shin Ichi; Hatta, Nobuaki; Harada, Mine.

:: Arthritis and Rheumatism, 巻 58, 番号 5, 01.05.2008, p. 1248-1257.

研究成果: ジャーナルへの寄稿記事

Mitoma, Hiroki ; Horiuchi, Takahiko ; Tsukamoto, Hiroshi ; Tamimoto, Yasuhiro ; kimoto, yasutaka ; Uchino, Ayumi ; To, Kentaro ; Harashima, Shin Ichi ; Hatta, Nobuaki ; Harada, Mine. / Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells : Comparison among infliximab, etanercept, and adalimumab. :: Arthritis and Rheumatism. 2008 ; 巻 58, 番号 5. pp. 1248-1257.
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title = "Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells: Comparison among infliximab, etanercept, and adalimumab",
abstract = "Objective. Three anti-tumor necrosis factor α (anti-TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFα 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-TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFα, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results. All of the anti-TNFα agents bound to transmembrane TNFα. 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 TNFα-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFα. Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside-to-inside signals by anti-TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.",
author = "Hiroki Mitoma and Takahiko Horiuchi and Hiroshi Tsukamoto and Yasuhiro Tamimoto and yasutaka kimoto and Ayumi Uchino and Kentaro To and Harashima, {Shin Ichi} and Nobuaki Hatta and Mine Harada",
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T1 - Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells

T2 - Comparison among infliximab, etanercept, and adalimumab

AU - Mitoma, Hiroki

AU - Horiuchi, Takahiko

AU - Tsukamoto, Hiroshi

AU - Tamimoto, Yasuhiro

AU - kimoto, yasutaka

AU - Uchino, Ayumi

AU - To, Kentaro

AU - Harashima, Shin Ichi

AU - Hatta, Nobuaki

AU - Harada, Mine

PY - 2008/5/1

Y1 - 2008/5/1

N2 - Objective. Three anti-tumor necrosis factor α (anti-TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFα 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-TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFα, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results. All of the anti-TNFα agents bound to transmembrane TNFα. 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 TNFα-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFα. Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside-to-inside signals by anti-TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

AB - Objective. Three anti-tumor necrosis factor α (anti-TNFα) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFα 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-TNFα agents by analyzing their biologic activities on transmembrane TNFα. Methods. Jurkat T cells stably expressing an uncleavable form of transmembrane TNFα were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFα, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFα estimated by apoptosis and cell cycle analysis using flow cytometry. Results. All of the anti-TNFα agents bound to transmembrane TNFα. 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 TNFα-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFα. Conclusion. Three different anti-TNF agents showed different biologic effects on transmembrane TNFα. This finding suggests that CDC and outside-to-inside signals by anti-TNFα antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.

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