Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance.
Agonistic antibodies against CD137 act as costimulators in the activation of CD8 T cells. They enhance the immune response against syngeneic tumour grafts and suppress T cell-dependent humoral immune responses in vivo. The present study was undertaken to determine whether suppression of antibody production by anti-CD137 mAb affects the development of collagen-induced arthritis (CIA). Male DBA/1J mice were immunized with bovine collagen II (CII) and treated with an agonistic anti-CD137 mAb or an isotype-matched control mAb. Mice were assessed regularly for macro- and microscopic signs of arthritis and for the appearance of collagen-specific antibody production. Interferon (IFN)-gamma determination, FACS analysis of splenocytes and histopathological joint examinations were performed after the animals were killed. Administration of anti-CD137 mAb at the time of collagen immunization blocked the development of disease and inhibited the humoral immune response against CII. Agonistic anti-CD137 mAb exhibited therapeutic efficacy even after the immune response to CII had succeeded and the disease became apparent. Furthermore, it induced a protective memory in the animals, enabling resistance to subsequent challenges with the pathogenic antigen. Our results suggest a key role for CD137 in the pathogenesis of CIA. This model provides insights into immunoregulatory conditions that control the pathogenesis of autoimmune diseases.
Foell
Juergen L
JL
University Children's Hospital, Eberhard Karls University, Tuebingen, Germany. juergen.foell@medizin.uni-halle.de
Diez-Mendiondo
Belkis I
BI
Diez
Oliver H
OH
Holzer
Ursula
U
Ruck
Peter
P
Bapat
Abhijit S
AS
Hoffmann
Michael K
MK
Mittler
Robert S
RS
Dannecker
Guenther E
GE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D024043:Collagen Type II / Q000276:immunology; D007113:Immunity, Innate; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; D024043:Collagen Type II; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma