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.
University Children's Hospital, Eberhard Karls University, Tuebingen, Germany. juergen.foell@medizin.uni-halle.de
Juergen L
JL
Foell
Belkis I
BI
Diez-Mendiondo
Oliver H
OH
Diez
Ursula
U
Holzer
Peter
P
Ruck
Abhijit S
AS
Bapat
Michael K
MK
Hoffmann
Robert S
RS
Mittler
Guenther E
GE
Dannecker
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