Immunological function of transmembrane TNF-alpha

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591172
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kyushu University
• Principal Investigator: HORIUCHI Takahiko Kyushu University, 医学研究院, 准教授 (90219212)
• Co-Investigator(Kenkyū-buntansha): 田平 知子 九州大学, 生体防御医学研究所, 助教 (50155230)
• Project Period (FY): 2008 – 2010
• Keywords: TNF / ADCC / CDC / サイトカイン / アポトーシス

Research Abstract

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 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.