权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Immunological function of transmembrane TNF-alpha

跨膜TNF-α的免疫功能

基本信息

批准号：
20591172
负责人：
HORIUCHI Takahiko
金额：
$ 3万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591172/
关键词：
TNF ADCC CDC サイトカインアポトーシス膜型TNF 可溶型TNF TNF阻害薬増殖 cDNA array 内向きシグナル

项目摘要

Transmembrane TNF-alpha, a precursor of soluble form of TNF-alpha (TNF), is expressed on activated macrophages and lymphocytes as well as other cell types. After processed by TNF-alpha-converting enzyme (TACE), soluble form of TNF is cleaved from transmembrane TNF and mediates its biological activities through binding to type 1 and type 2 TNF receptors (TNF-R1, TNF-R2) of remote tissues. Accumulating evidence suggests that not only soluble TNF, but also transmembrane TNF is involved in the inflammatory response. TNF antagonists are the center of attention for their dramatic clinical efficacy in active chronic inflammatory diseases. In rheumatoid arthritis, both infliximab (chimeric anti-TNF antibody), adalimumab (humanized anti-TNF-alpha antibody) and etanercept (p75 TNF-alpha receptor-IgG Fc fusion protein) are highly effective, while in Crohn's disease, only infliximab and adalimumab can induce clinical remission. In addition, infliximab and adalimumab are more prone to cause granulo … More matous infections such as tuberculosis. Considering the important role of transmembrane TNF in granulomatous inflammation, analysing the biology of transmembrane TNF and its interaction with TNF antagonists will contribute to understand the bases for differential clinical efficacies of these promising treatment modalities.Infliximab, adalimumab, and etanercept similarly induced antibody-dependent dell-mediated cytotoxicity (ADCC) in transmembrane TNF-expressing human T cells, however only infliximab and adalimumab showed complement-dependent cytotoxicity (CDC) and outside-to-inside signal (reverse signal) and etanercept did not. In addition, the function of transmembrane TNF as a ligand detected by cytotoxic activity against TNF recetor-bearing T cells was effectively inhibited by infliximab and adalimumab, but not by etanercept. cDNA array revealed the intracellular signals mediated by infliximab through transmembrane TNF. mRNA of 49 molecules was upregulated, while mRNA of 240 molecules was downregulated.These results indicate that the difference in the activity against transmembrane TNF among TNF antagonists (infliximab, adalimumab, etanercept) is involved in the differential clinical efficacies of these TNF antagonists. Less

跨膜TNF-α是可溶性TNF-α（TNF）的前体，在活化的巨噬细胞和淋巴细胞以及其他细胞类型上表达。可溶性TNF经TNF-α转化酶（TACE）处理后，从跨膜TNF上裂解下来，并通过与远处组织的1型和2型TNF受体（TNF-R1、TNF-R2）结合来介导其生物学活性。越来越多的证据表明，不仅可溶性TNF，而且跨膜TNF参与炎症反应。TNF拮抗剂因其在活动性慢性炎性疾病中的显著临床疗效而成为关注的中心。在类风湿性关节炎中，英夫利西单抗（嵌合抗TNF抗体）、阿达木单抗（人源化抗TNF-α抗体）和依那西普（p75 TNF-α受体-IgG Fc融合蛋白）均高度有效，而在克罗恩病中，只有英夫利西单抗和阿达木单抗可诱导临床缓解。此外，英夫利西单抗和阿达木单抗更容易引起肉芽肿 ...更多信息肿瘤感染，如肺结核。考虑到跨膜TNF在肉芽肿性炎症中的重要作用，分析跨膜TNF的生物学及其与TNF拮抗剂的相互作用将有助于理解这些有前途的治疗方式的不同临床疗效的基础。英夫利昔单抗、阿达木单抗和依那西普在表达跨膜TNF的人T细胞中类似地诱导抗体依赖性dell介导的细胞毒性（ADCC），然而，只有英夫利昔单抗和阿达木单抗显示补体依赖性细胞毒性（CDC）和由外向内信号（反向信号），而依那西普没有。此外，通过对携带TNF受体的T细胞的细胞毒活性检测到跨膜TNF作为配体的功能，英夫利昔单抗和阿达木单抗可有效抑制，但依那西普不能抑制。cDNA阵列显示了英夫利西单抗通过跨膜TNF介导的细胞内信号。49个分子的mRNA表达上调，而240个分子的mRNA表达下调。这些结果表明，TNF拮抗剂（英夫利昔单抗，阿达木单抗，依那西普）之间的跨膜TNF活性的差异涉及这些TNF拮抗剂的临床疗效的差异。少