4-1BB-mediated immunotherapy of rheumatoid arthritis

  • A Corrigendum to this article was published on 01 November 2004


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.


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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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