Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease.
Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-gamma production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor-independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.
Sun
Yonglian
Y
Department of Pathology and Committee in Immunology, University of Chicago, Chicago, Illinois, USA.
Chen
Helen M
HM
Subudhi
Sumit K
SK
Chen
Jonathan
J
Koka
Rima
R
Chen
Lieping
L
Fu
Yang-Xin
YX
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D001323:Autoantibodies / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019014:fas Receptor / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019014:fas Receptor; D007371:Interferon-gamma