Author: ["Su K Seo","Jae H Choi","Young H Kim","Woo J Kang","Hye Y Park","Jae H Suh","Beom K Choi","Dass S Vinay","Byoung S Kwon"]
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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.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 