Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis.
Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-alpha MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4(+) T cell infiltration in the colon and suppressed IFN-gamma, IL-2, and TNF-alpha production by lamina propria CD4(+) T cells. The combination with anti-TNF-alpha MAb further improved the therapeutic effect by abolishing IFN-gamma, IL-2, and TNF-alpha production by lamina propria CD4(+) T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-alpha blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.
Totsuka
T
T
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Kanai
T
T
Uraushihara
K
K
Iiyama
R
R
Yamazaki
M
M
Akiba
H
H
Yagita
H
H
Okumura
K
K
Watanabe
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D053278:OX40 Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D048069:Tumor Necrosis Factors
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C406562:OX40Ig; C504586:Tnfsf4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors