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Immunological function of transmembrane TNF-alpha

Research Project

Project/Area Number 20591172
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionKyushu 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
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
KeywordsTNF / 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
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 … 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

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (12 results)

All 2010 2009 2008

All Journal Article (9 results) (of which Peer Reviewed: 9 results) Presentation (3 results)

  • [Journal Article] Transmembrane TNF-α. Structure, function and interaction with anti-TNF agents.2010

    • Author(s)
      Horiuchi T, Mitoma H, et al.
    • Journal Title

      Rheumatology (Oxford)

      Volume: 49(7) Pages: 1225-1228

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of killer cell immunoglobulin-like receptor 2DL5 with systemic lupus erythematosus and accompanying infections.2010

    • Author(s)
      Kimoto Y, Horiuchi T, et al.
    • Journal Title

      Rheumatology (Oxford)

      Volume: 49(7) Pages: 1346-1353

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese.2010

    • Author(s)
      Nishimoto K, Horiuchi T, et al.
    • Journal Title

      Ann.Rheum.Dis.

      Volume: 69(2) Pages: 363-373

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Combination of TNF-RII, CYP1A1and GSTM1 polymorphisms and the risk of Japanese SLE : findings from the KYSS study2009

    • Author(s)
      Horiuchi T, et al.
    • Journal Title

      Rheumatology(Oxford) 48

      Pages: 1045-9

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cigarette smoking, STAT4 and TNFRSF1B polymorphisms, and SLE in a Japanese population2009

    • Author(s)
      Kiyohara C, et al.
    • Journal Title

      J Rheumatol 36

      Pages: 2195-203

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cigarette smoking, N-acetyltransferase 2 polymorphisms and SLE in a Japanese population2009

    • Author(s)
      Kiyohara C, et al.
    • Journal Title

      Lupus 18

      Pages: 630-8

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanisms for cytotoxic effects of anti-TNF agents on transmembrane TNF-expressing cells : comparison among infliximab, etanercept and adalimumab.2008

    • Author(s)
      Mitoma H, Horiuchi T, et al.
    • Journal Title

      Arthritis Rheum 58(5)

      Pages: 1248-1257

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of polymorphisms in complement component C3 gene with susceptibility to systemiclupus erythematosus.2008

    • Author(s)
      Miyagawa H, Horiuchi T, et al.
    • Journal Title

      Rheumatology (Oxford) 47

      Pages: 158-164

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans' syndrome : Immunological analysis of B cells, T cells and cytokines.2008

    • Author(s)
      Tamimoto Y, Horiuchi T, et al.
    • Journal Title

      Rheumatology (Oxford) 47

      Pages: 821-827

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] 抗TNF製剤の作用機序:その共通点と相違点2010

    • Author(s)
      堀内孝彦
    • Organizer
      第54回日本リウマチ学会総会
    • Place of Presentation
      神戸
    • Year and Date
      2010-04-24
    • Related Report
      2010 Annual Research Report
  • [Presentation] ループス腎炎に対する宅ロリムすの有効性と安全性-投与開始後1年経過した29例の解析-2009

    • Author(s)
      堀内孝彦
    • Organizer
      日本リウマチ学会
    • Place of Presentation
      東京
    • Year and Date
      2009-04-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] ループス腎炎の維持療法としてのタクロリムスの有効性と安全既2008

    • Author(s)
      堀内孝彦
    • Organizer
      第23回日本臨床リウマチ学会総会
    • Place of Presentation
      横浜
    • Year and Date
      2008-11-29
    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2019-02-28  

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