4-1BB-mediated immunotherapy of rheumatoid arthritis

Nat Med. 2004 Oct;10(10):1088-94. doi: 10.1038/nm1107. Epub 2004 Sep 26.


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-gamma 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-gamma produced by these cells suppresses antigen-specific CD4(+) T cells through an indoleamine 2,3-dioxygenase-dependent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / physiopathology
  • Arthritis, Rheumatoid / therapy*
  • CD11 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8 Antigens / immunology
  • Collagen Type II / immunology
  • DNA Primers
  • Dendritic Cells / immunology
  • Immunohistochemistry
  • Immunotherapy*
  • Mice
  • Monocytes / immunology
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / immunology
  • Tryptophan Oxygenase / immunology
  • Tryptophan Oxygenase / metabolism
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antibodies, Monoclonal
  • Antigens, CD
  • CD11 Antigens
  • CD8 Antigens
  • Collagen Type II
  • DNA Primers
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tryptophan Oxygenase