Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis.
OX40 ligand (OX40L) and OX40 (CD134) are a pair of cell surface molecules belonging to the TNF/TNF receptor family. Interaction of OX40L with its receptor OX40 is thought to be important in T cell activation through T cell/antigen-presenting cell interaction. However, involvement of these molecules in the pathogenesis of rheumatoid arthritis (RA) remains unclear. To explore the contribution of OX40/OX40L interaction to the pathogenesis of RA in vivo, we evaluated the effect of a neutralizing anti-OX40L monoclonal antibody (mAb) on the development of collagen-induced arthritis (CIA) in DBA/1 mice as an animal model for RA. Administration of anti-OX40L mAb into type II collagen (CII) -immunized DBA/1 mice dramatically ameliorated the disease severity. In vivo treatment with anti-OX40L mAb did not inhibit the expansion of CII-reactive T cells, but suppressed IFN-gamma and anti-CII IgG2a production. Therefore, OX40/OX40L interaction appears to play a critical role in the development of CIA by enhancing Th1-type autoimmune response. In addition, T lymphocytes in synovial fluid and synovial tissue from RA patients expressed OX40, while OX40L was expressed on sublining cells in synovial tissue. These results indicate that OX40/OX40L interaction may play a critical role in the development of RA.
Yoshioka
T
T
Department of Joint Disease and Rheumatism, Nippon Medical School, Tokyo, Japan.
Nakajima
A
A
Akiba
H
H
Ishiwata
T
T
Asano
G
G
Yoshino
S
S
Yagita
H
H
Okumura
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D003094:Collagen / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008811:Mice, Inbred DBA; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000502:physiology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology* / Q000502:physiology; D048069:Tumor Necrosis Factors
D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505716:TNFRSF4 protein, human; C089251:TNFSF4 protein, human; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D003094:Collagen