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.
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.