4-1BB-mediated immunotherapy of rheumatoid arthritis

  • 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.

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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.

References

  1. 1

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

  2. 2

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

  3. 3

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

  4. 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).

  5. 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).

  6. 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).

  7. 7

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

  8. 8

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

  9. 9

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

  10. 10

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

  11. 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).

  12. 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).

  13. 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).

  14. 14

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

  15. 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).

  16. 16

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

  17. 17

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

  18. 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).

  19. 19

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

  20. 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).

  21. 21

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

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 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).

  27. 27

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

  28. 28

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

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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.

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Correspondence to Byoung S Kwon.

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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)

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

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