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mAbs in a murine model of chronic colitis
1 Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
2 Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: taka.gast{at}tmd.ac.jp.
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+CD45RBhigh T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-
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-
, IL-2, and TNF- production by lamina propria CD4+ T cells. The combination with anti-TNF- mAb further improved the therapeutic effect by abolishing IFN-, IL-2, and TNF- 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- blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.
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