Anti-CD137 mAb treatment inhibits experimental autoimmune uveitis by limiting expansion and increasing apoptotic death of uveitogenic T cells

Invest Ophthalmol Vis Sci. 2005 Feb;46(2):596-603. doi: 10.1167/iovs.04-0835.

Abstract

Purpose: To explore the role of CD137 in the pathogenesis of experimental autoimmune uveitis (EAU) and to compare the inhibitory mechanism of anti-CD137 mAb with other costimulatory blockers.

Methods: EAU was induced in B10RIII mice, either by immunization with a uveitogenic peptide, IRBP161-180, derived from the interphotoreceptor retinoid-binding protein, or by adoptive transfer of IRBP161-180-specific T cells. The effect of an agonistic anti-CD137 mAb (2A) on the in vivo induction of disease was studied. Subsequently, the mechanism by which anti-CD137 mAb inhibits uveitogenic T-cell activation was investigated, by using the adoptive transfer of T cells derived from anti-CD137 mAb-treated mice, and in vitro, using the proliferative response and apoptotic cell death of IRBP-specific T cells from anti-CD137 mAb-treated mice.

Results: Administration of anti-CD137 mAb prevented the development of de novo induced uveitis, but not that induced by adoptive transfer of pathogenic T cells. Furthermore, anti-CD137 mAb treatment of the animals resulted in decreased expansion of uveitogenic T cells, accompanied by increased activated cell death and resistance to reinduction of uveitis.

Conclusions: CD137 plays a critical role in the induction, rather than the effector, phase of the disease. Different costimulatory molecules have different effects on the activation of autoreactive T cells by acting in different phases of T-cell activation.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD / immunology*
  • Apoptosis / drug effects*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / prevention & control*
  • Cell Proliferation
  • Eye Proteins / immunology
  • Female
  • Immunization
  • Lymphocyte Activation
  • Mice
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Retinol-Binding Proteins / immunology
  • Specific Pathogen-Free Organisms
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Uveitis, Posterior / immunology
  • Uveitis, Posterior / pathology
  • Uveitis, Posterior / prevention & control*

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Eye Proteins
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Retinol-Binding Proteins
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • interstitial retinol-binding protein