Anti-CD137 mAb treatment inhibits experimental autoimmune uveitis by limiting expansion and increasing apoptotic death of uveitogenic T cells.
OBJECTIVE
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.
Shao
Hui
H
Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, Kentucky 40202, USA.
Fu
Yangxin
Y
Liao
Tianjiang
T
Peng
Young
Y
Chen
Lieping
L
Kaplan
Henry J
HJ
Sun
Deming
D
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D005136:Eye Proteins / Q000276:immunology; D005260:Female; D007114:Immunization; D008213:Lymphocyte Activation; D051379:Mice; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D012177:Retinol-Binding Proteins / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D015866:Uveitis, Posterior / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D005136:Eye Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D012177:Retinol-Binding Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000099214:Retinol-Binding Proteins, Interstitial; C505715:Tnfrsf9 protein, mouse