Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance

Immunology. 2004 Sep;113(1):89-98. doi: 10.1111/j.1365-2567.2004.01952.x.


Agonistic antibodies against CD137 act as costimulators in the activation of CD8 T cells. They enhance the immune response against syngeneic tumour grafts and suppress T cell-dependent humoral immune responses in vivo. The present study was undertaken to determine whether suppression of antibody production by anti-CD137 mAb affects the development of collagen-induced arthritis (CIA). Male DBA/1J mice were immunized with bovine collagen II (CII) and treated with an agonistic anti-CD137 mAb or an isotype-matched control mAb. Mice were assessed regularly for macro- and microscopic signs of arthritis and for the appearance of collagen-specific antibody production. Interferon (IFN)-gamma determination, FACS analysis of splenocytes and histopathological joint examinations were performed after the animals were killed. Administration of anti-CD137 mAb at the time of collagen immunization blocked the development of disease and inhibited the humoral immune response against CII. Agonistic anti-CD137 mAb exhibited therapeutic efficacy even after the immune response to CII had succeeded and the disease became apparent. Furthermore, it induced a protective memory in the animals, enabling resistance to subsequent challenges with the pathogenic antigen. Our results suggest a key role for CD137 in the pathogenesis of CIA. This model provides insights into immunoregulatory conditions that control the pathogenesis of autoimmune diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • Arthritis, Experimental / prevention & control*
  • Arthritis, Experimental / therapy
  • Autoantibodies / biosynthesis
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / prevention & control*
  • Autoimmune Diseases / therapy
  • Collagen Type II / immunology
  • Immunity, Innate
  • Immunophenotyping
  • Interferon-gamma / biosynthesis
  • Male
  • Mice
  • Mice, Inbred DBA
  • Receptors, Nerve Growth Factor / antagonists & inhibitors*
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor / immunology
  • Spleen / immunology
  • T-Lymphocyte Subsets / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9


  • Antibodies, Monoclonal
  • Antigens, CD
  • Autoantibodies
  • Collagen Type II
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interferon-gamma