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.

  • Article
  • Published:

4-1BB-mediated immunotherapy of rheumatoid arthritis

Nature Medicine volume 10, pages 1088–1094 (2004)Cite this article

A Corrigendum to this article was published on 01 November 2004

Abstract

Collagen type II–induced arthritis is a CD4+ T-cell–dependent chronic inflammation in susceptible DBA/1 mice and represents an animal model of human rheumatoid arthritis. We found that development of this condition, and even established disease, are inhibited by an agonistic anti-4-1BB monoclonal antibody. Anti-4-1BB suppressed serum antibodies to collagen type II and CD4+ T-cell recall responses to collagen type II. Crosslinking of 4-1BB evoked an antigen-specific, active suppression mechanism that differed from the results of blocking the interaction between 4-1BB and its ligand, 4-1BBL. Anti-4-1BB monoclonal antibodies induced massive, antigen-dependent clonal expansion of CD11c+CD8+ T cells and accumulation of indoleamine 2,3-dioxygenase in CD11b+ monocytes and CD11c+ dendritic cells. Both anti-interferon-γ and 1-methyltryptophan, a pharmacological inhibitor of indoleamine 2,3-dioxygenase, reversed the anti-4-1BB effect. We conclude that the suppression of collagen-induced arthritis was caused by an expansion of new CD11c+CD8+ T cells, and that interferon-γ produced by these cells suppresses antigen-specific CD4+ T cells through an indoleamine 2,3-dioxygenase–dependent mechanism.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Agonistic anti-4-1BB monoclonal antibodies suppress development of CIA, established CIA, and CII-specific CD4+ T cell proliferation.
Figure 2: Anti-4-1BB treatment induces expansion of a CD11c+CD8+ T cell population not previously reported.
Figure 3: Kinetics of expansion and characteristics of the CD11c+CD8+ T cells.
Figure 4: Adoptive transfer of CD11c+CD8+ T cells suppresses CIA.
Figure 5: IFN-γ mediates anti-4-1BB effects.
Figure 6: Anti-IFN-γ and 1-MT reverse 4-1BB-mediated suppression of CIA.

Similar content being viewed by others

References

  1. Zvaifler, N.J. Pathogenesis of the joint disease of rheumatoid arthritis. Am. J. Med. 75, 3–8 (1983).

    Article  CAS  Google Scholar 

  2. Arend, W.P. The pathophysiology and treatment of rheumatoid arthritis. Arthritis Rheum. 40, 595–597 (1997).

    Article  CAS  Google Scholar 

  3. Bresnihan, B. et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 41, 2196–2204 (1998).

    Article  CAS  Google Scholar 

  4. 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 

  5. Holmdahl, R., Brockermann, R., Bäcklund, J. & Yamada, H. The molecular pathogenesis of collagen-induced arthritis in mice – a model for rheumatoid arthritis. Ageing Res. Rev. 1, 135–147 (2002).

    Article  CAS  Google Scholar 

  6. Williams, R.O., Mason, L.J., Feldmann, M. & Maini, R.N. Synergy between anti-CD4 and anti-TNF in the amelioration of established collagen-induced arthritis. Proc. Natl. Acad. Sci. USA 92, 2762–2766 (1994).

    Article  Google Scholar 

  7. Kwon, B.S. & Weissman, S.M. cDNA sequences of two inducible T-cell genes. Proc. Natl. Acad. Sci. USA 86, 1963–1967 (1989).

    Article  CAS  Google Scholar 

  8. Pollok, K.E. et al. Inducible T cell antigen 4-1BB. Analysis of expression and function. J. Immunol. 150, 771–781 (1993).

    CAS  PubMed  Google Scholar 

  9. Melero, I. et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med. 3, 682–685 (1997).

    Article  CAS  Google Scholar 

  10. Ye, Z. et al. Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat. Med. 8, 343–348 (2002).

    Article  CAS  Google Scholar 

  11. Halstead, E.S., Mueller, Y.M., Altman, J.D. & Katsikis, P.D. In vivo stimulation of CD137 broadens primary antiviral CD8+ T cell responses. Nat. Immunol. 3, 536–541 (2002).

    Article  CAS  Google Scholar 

  12. Bertram, E.M., Lau, P. & Watts, T.H. Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. J. Immunol. 168, 3777–3785 (2002).

    Article  CAS  Google Scholar 

  13. Mittler, R.S., Bailey, T.S., Klussman, K., Trailsmith, M.D. & Hoffmann, M.K. Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J. Exp. Med. 190, 1535–1540 (1999).

    Article  CAS  Google Scholar 

  14. Sun, Y. et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat. Med. 8, 1404–1413 (2003).

    Google Scholar 

  15. Foell, J. et al. CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB × NZW F1 mice. J. Clin. Invest. 111, 1505–1518 (2003).

    Article  CAS  Google Scholar 

  16. Munn, D.H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).

    Article  CAS  Google Scholar 

  17. Grohmann, U. et al. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).

    Article  CAS  Google Scholar 

  18. Mellor, A.L. et al. Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J. Immunol. 171, 1652–1655 (2003).

    Article  CAS  Google Scholar 

  19. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    Article  CAS  Google Scholar 

  20. Mauri, C., Mars, L.T. & Londei, M. Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process. Nat. Med. 6, 673–679 (2000).

    Article  CAS  Google Scholar 

  21. Mellor, A.L. & Munn, D.H. Tryptophan catabolism and regulation of adaptive immunity. J. Immunol. 170, 5809–5813 (2003).

    Article  CAS  Google Scholar 

  22. Terness, P. et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447–457 (2002).

    Article  CAS  Google Scholar 

  23. Nakajima, H., Takamori, H., Hiyama, Y. & Tsukada, W. The effect of treatment with interferon-gamma on type II collagen-induced arthritis. Clin. Exp. Immunol. 81, 441–445 (1990).

    Article  CAS  Google Scholar 

  24. Futagawa, T. et al. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int. Immunol. 14, 275–286 (2002).

    Article  CAS  Google Scholar 

  25. Myers, L. et al. CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering. Proc. Natl. Acad. Sci. USA 100, 5348–5353 (2003).

    Article  CAS  Google Scholar 

  26. Shuford, W.W. et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55 (1997).

    Article  CAS  Google Scholar 

  27. Milliken, G.A. & Johnson, D.E. Analysis of Messy Data. Volume I: Designed Experiments (Van Nostrand Reinhold Company, New York, 1984).

    Google Scholar 

  28. Edwards, D. & Berry, J.J. The efficiency of simulation-based multiple comparisons. Biometrics 43, 913–928 (1987).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Thompson at the LSU Eye Center for statistical analysis. This research was supported by NIH grants R01EY013325 (BSK) and P30EY002377 (departmental Core grant), and the Science Research Center Fund to the Immunomodulation Research Center at the University of Ulsan from KOSEF and the Korean Ministry of Science and Technology.

Author information

Authors and Affiliations

  1. The Immunomodulation Research Center, University of Ulsan, 29 Mukeo-Dong, Nam-ku, Ulsan, 680-749, Korea

    Su K Seo, Jae H Choi, Young H Kim, Woo J Kang, Hye Y Park, Beom K Choi & Byoung S Kwon

  2. Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, 290-3 Jeonha-Dong, Dong-ku, Ulsan, 682-060, Korea

    Jae H Suh

  3. LSU Eye Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite B, New Orleans, 70112-2234, Louisiana, USA

    Dass S Vinay & Byoung S Kwon

Authors
  1. Su K Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae H Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young H Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Woo J Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hye Y Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jae H Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Beom K Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dass S Vinay
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Byoung S Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byoung S Kwon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Agonistic anti-4-1BB mAb suppresses development of CIA. (PDF 62 kb)

Supplementary Fig. 2

Histology of ankle joint. (PDF 166 kb)

Supplementary Fig. 3

Production of anti-CII antibodies. (PDF 63 kb)

Supplementary Fig. 4

Phenotypic analysis of CD11c+CD8+CD3+ T cells. (PDF 247 kb)

Supplementary Fig. 5

DNA content of CD11c+CD8+ T cells. (PDF 50 kb)

Supplementary Methods (PDF 22 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seo, S., Choi, J., Kim, Y. et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 10, 1088–1094 (2004). https://doi.org/10.1038/nm1107

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1107

This article is cited by

Search

Advanced 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