Novel regulatory mechanism of human Toll-like receptor 4 function by the inhibitory monoclonal antibody

抑制性单克隆抗体调控人Toll样受体4功能的新机制

• 批准号: 24790112
• 负责人: TSUKAMOTO HIROKI
• 金额: $ 2.91万
• 依托单位: Tohoku University (2013)Saga University (2012)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24790112/
• 关键词: TLR4; MD-2; リポ多糖; モノクローナル抗体; 敗血症; 抗体医薬; 免疫学

In this study, novel inhibitory monoclonal antibodies against human Toll-like receptor 4 (TLR4), which are potential leading antibodies for anti-sepsis antibody drugs, were developed. These antibodies inhibited the production of proinflammatory cytokines, the upregulation of costimulatory molecules and the activation of NF-kappaB in lipopolysaccharide (LPS)-stimulated cells such as human peripheral blood mononuclear cells. The inhibitory activities were mediated by novel mechanism that is the induction of inactive TLR4 oligomerization, the inhibition of LPS-induced TLR4 internalization, but not the inhibition of TLR4-LPS binding. In addition, the epitope to which the binding of antibody inhibits the TLR4 function was found on extracellular domain of TLR4 independently of MD-2. Identification and chracterization of this epitope may provide a promising drug discovery target sturucture for the development of anti-septic antibody drugs.

本研究开发了新型的抗人Toll样受体4（TLR 4）的抑制性单克隆抗体，这是抗脓毒症抗体药物的潜在先导抗体。这些抗体抑制促炎细胞因子的产生、共刺激分子的上调和脂多糖（LPS）刺激的细胞（如人外周血单核细胞）中NF-κ B的活化。其抑制活性是通过新的机制介导的，即诱导失活的TLR 4寡聚化，抑制LPS诱导的TLR 4内化，但不抑制TLR 4-LPS结合。另外，抗体结合抑制TLR 4功能的表位独立于MD-2在TLR 4的胞外结构域上发现。该表位的鉴定和表征为抗脓毒症抗体药物的开发提供了一个很有前景的药物发现靶点结构。

项目成果

Inhibition of antibody production in vivo by pre-stimulation of Toll-like receptor 4 before antigen priming is caused by defective B cell priming and not impairment in antigen presentation.

在抗原引发前预刺激 Toll 样受体 4 抑制体内抗体产生是由 B 细胞引发缺陷引起的，而不是抗原呈递受损所致。

• DOI: 10.1093/intimm/dxs096
• 发表时间: 2013
• 期刊: International Immunology
• 影响因子: 4.4
• 作者: Nurlaely Mida Rachmawati;Kenji Fukudome;Naoko Tsuneyoshi;Uleng Bahrun;Hiroki Tsukamoto;Tsutomu Yanagibashi;Yoshinori Nagai;Kiyoshi Takatsu;Shoichiro Ohta;and Masao Kimoto
• 通讯作者: and Masao Kimoto

A validated quantitative liquid chromatography-tandem quadrupole mass spectrometry method for monitoring isotopologues to evaluate global modified cytosine ratios in genomic DNA

• DOI: 10.1016/j.jchromb.2014.01.050
• 发表时间: 2014-03-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Tsuji, Makoto;Matsunaga, Hironori;Tomioka, Yoshihisa
• 通讯作者: Tomioka, Yoshihisa

Enzymatic synthesis of di-fucosylated chitooligosaccharide by human and rhizobiaα1,6-fucosyltransferases

人和根瘤菌α1,6-岩藻糖基转移酶酶促合成二岩藻糖基化壳寡糖

• 发表时间: 2012
• 作者: Ihara H;Hanashima S;Tsukamoto H;Yamaguchi Y;Taniguchi N;Ikeda Y
• 通讯作者: Ikeda Y

A delicate balance: CD73-generated adenosine limits the severity of graft vs. host disease but also constrains the allogeneic graft vs. tumor effect.

• DOI: 10.4161/onci.22107
• 发表时间: 2013-01-01
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Thompson LF;Tsukamoto H;Chernogorova P;Zeiser R
• 通讯作者: Zeiser R

Reduced surface expression of TLR4 by a V254I point mutation may account for the low LPS responder phenotype of BALB/c B cells

V254I 点突变导致 TLR4 表面表达减少可能是 BALB/c B 细胞低 LPS 反应表型的原因

• 发表时间: 2012
• 作者: Tsukamoto H;Fukudome K;Takao S;Tsuneyoshi N;Ohta S;Nagai Y;Ihara H;Miyake K;Ikeda Y;Kimoto M
• 通讯作者: Kimoto M