CD137-mediated T cell co-stimulation terminates existing autoimmune disease in SLE-prone NZB/NZW F1 mice.
T cell receptor recognition of antigen and major histocompatibility complex (signal 1) and T cell co-stimulation (signal 2) are essential for full T cell activation, differentiation, and survival of naïve and activated T cells. The proto-typical T cell co-stimulatory receptor, CD28, is a constitutively expressed type I integral transmembrane protein and member of the Ig superfamily. Since its discovery, additional T cell co-stimulatory receptors have been identified, a number of which belong to the tumor necrosis factor receptor superfamily. Included within this group is CD137 (4-1BB), an activation-inducible, type I transmembrane protein. Co-stimulation of T cells through CD137 effectively up-regulates CD8 T cell activation and survival. Although CD4(+) T cells are efficiently activated through the T cell receptor and CD137 receptor, it provokes CD4(+) T cell anergy and blockade of T-dependent humoral immune responses. Therefore, we tested whether agonistic anti-CD137 monoclonal antibodies (mAbs) would be effective in blocking the induction or progression of B cell dependent autoimmune disease. Herein, we demonstrate the protective effect of agonistic anti-CD137 mAbs in blocking systemic lupus erythematosus (SLE) disease progression in NZB/W F1 mice. Protection from SLE following anti-CD137 mAb treatment is not confined to rescuing mice from disease progression; rather, it fully protects young mice from developing any symptoms of disease. We further found that treatment of proteinuric mice with anti-CD137 blocks ongoing anti-dsDNA autoantibody production.
Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
Juergen
J
Foell
Megan
M
McCausland
Jennifer
J
Burch
Nicholas
N
Corriazzi
Xiao-Jie
XJ
Yan
Carolyn
C
Suwyn
Shawn P
SP
O'Neil
Michael K
MK
Hoffmann
Robert S
RS
Mittler
D000818:Animals; D015703:Antigens, CD; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D004198:Disease Susceptibility; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051379:Mice; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9