Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases

An Erratum to this article was published on 01 November 2003

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Top, Marc Feldmann and Ravinder Maini (2000).
Figure 2: TNF-α-dependent cytokine cascade.
Figure 3: Monoclonal antibodies and TNFreceptor fusion protein bind TNF and block its access to TNF receptors on the surface of target cells in joints.

References

  1. Klareskog, L., Forsum, U., Scheynius, A., Kabelitz, D. & Wigzell, H. Evidence in support of a self perpetuating HLA-DR dependent delayed type cell reaction in rheumatoid arthritis. Proc. Natl. Acad. Sci. USA 72, 3632–3636 (1982).

    Article  Google Scholar 

  2. Janossy, G. et al. Rheumatoid arthritis: a disease of T-lymphocyte/macrophage immunoregulation. Lancet 2, 839–842 (1981).

    Article  CAS  Google Scholar 

  3. Bottazzo, G.F., Pujol-Borrell, R., Hanafusa, T. & Feldmann, M. Role of aberrant HLA-DR expression and antigen presentation in the induction of endocrine autoimmunity. Lancet 2, 1115–1119 (1983).

    Article  CAS  Google Scholar 

  4. Taniguchi, T. et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 302, 305–310 (1983).

    Article  CAS  Google Scholar 

  5. Pennica, D. et al. Human tumor necrosis factor: precursor structure expression and homology to lymphotoxin. Nature 312, 724–729 (1984).

    Article  CAS  Google Scholar 

  6. Yasukawa, L. et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6 gene). EMBO J. 6, 2939–2945 (1987).

    Article  CAS  Google Scholar 

  7. Feldmann, M., Brennan, F.M. & Maini, R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).

    Article  CAS  Google Scholar 

  8. Buchan, G. et al. Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 alpha. Clin. Exp. Immunol. 73, 449–455 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Brennan, F.M., Chantry, D., Jackson, A., Maini, R. & Feldmann, M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin- 1 production in rheumatoid arthritis. Lancet 2, 244–247 (1989).

    Article  CAS  Google Scholar 

  10. Haworth, C. et al. Expression of granulocyte-macrophage colony-stimulating factor in rheumatoid arthritis: regulation by tumor necrosis factor-alpha. Eur. J. Immunol. 21, 2575–2579 (1991).

    Article  CAS  Google Scholar 

  11. Fong, Y. et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1β and interleukin 6 appearance during lethal bacteremia. J. Exp. Med. 170, 1627–1633 (1989).

    Article  CAS  Google Scholar 

  12. Chu, C.Q., Field, M., Feldmann, M. & Maini, R.N. Localization of tumor necrosis factor α in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34, 1125–1132 (1991).

    Article  CAS  Google Scholar 

  13. Williams, R.O., Feldmann, M. & Maini, R.N. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. USA 89, 9784–9788 (1992).

    Article  CAS  Google Scholar 

  14. Keffer, J. et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991).

    Article  CAS  Google Scholar 

  15. Tracey, K.J. et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664 (1987).

    Article  CAS  Google Scholar 

  16. Elliott, M.J. et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 36, 1681–1690 (1993).

    Article  CAS  Google Scholar 

  17. Elliott, M.J. et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125–1127 (1994).

    Article  CAS  Google Scholar 

  18. Elliott, M.J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).

    Article  CAS  Google Scholar 

  19. Maini, R.N. et al. Randomized placebo-controlled trial of multiple intravenous infusions of anti-TNFα monoclonal antibody with or without weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 (1998).

    Article  CAS  Google Scholar 

  20. Williams, R.O., Mason, L.J., Feldmann, M. & Maini, R.N. Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. Proc. Natl. Acad. Sci. USA 91, 2762–2766 (1994).

    Article  CAS  Google Scholar 

  21. Moreland, L.W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).

    Article  CAS  Google Scholar 

  22. Weinblatt, M.E. et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibodiy, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  Google Scholar 

  23. ATTRACT Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N. Engl. J. Med. 343, 1594–1602 (2000).

  24. ATTRACT Study Group. Sustained improvement in physical function, structural damage, and signs and symptom through 2 years in rheumatoid arthritis patients treated with infliximab (Remicade) and methotrexate. Arthritis Rheum. (in the press).

  25. Charles, P. et al. Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J. Immunol. 163, 1521–1528 (1999).

    CAS  PubMed  Google Scholar 

  26. Taylor, P.C. et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor α blockade in patients with rheumatoid arthritis. Arthritis Rheum. 43, 38–47 (2000).

    Article  CAS  Google Scholar 

  27. Paleolog, E.M. et al. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum. 41, 1258–1265 (1998).

    Article  CAS  Google Scholar 

  28. Day, R. Adverse reactions to TNFα inhibitors in rheumatoid arthritis. Lancet 359, 540–541 (2002).

    Article  Google Scholar 

  29. Arend, W.P. & Dayer, J.-M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor α in rheumatoid arthritis. Arthritis Rheum. 38, 151–160 (1995).

    Article  CAS  Google Scholar 

  30. Nishimoto, N. et al. Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J. Rheumatol. 30, 1426–1435 (2003).

    CAS  PubMed  Google Scholar 

  31. Feldmann, M. & Maini, R.N. Anti-TNFα therapy or rheumatoid arthritis: What have we learned? Annu. Rev. Immunol. 19, 163–196 (2001).

    Article  CAS  Google Scholar 

  32. van Dullemen, H.M. et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129–135 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Receiving a prize such as this promotes reflection. We could not have done this work without the highly productive and enjoyable association with each other over 20 years, and enormous support from many directions. We thank our families and wives (Tania and Geraldine), our assistants and our local and international scientific and clinical colleagues: those named in the text and, in particular, F. Breedveld, J. Kalden, J. Smolen, E. Paleolog, P. Charles, M. Elliott, P. Taylor; our clinical trial collaborators; research nurses; and collaborators at Centocor, in particular J. Woody, H. Weissman, J. Ghrayeb and T. Schaible. Most importantly, this could not have been accomplished without extensive financial support, which for us has been dominated by the British charities supporting arthritis research, arc (Arthritis Research Campaign) and the Kennedy Institute of Rheumatology Trust.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Feldmann, M., Maini, R. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 9, 1245–1250 (2003). https://doi.org/10.1038/nm939

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm939

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing