title: Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease.
abstract: 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.
authors.affiliation: Department of Pathology and Committee in Immunology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Yonglian
authors.initials: Y
authors.lastname: Sun
authors.forename: Helen M
authors.initials: HM
authors.lastname: Chen
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Subudhi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chen
authors.forename: Rima
authors.initials: R
authors.lastname: Koka
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: 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
chemical_list: 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