Therapeutic effect of anti-OX40L and anti-TNF- MAbs in a murine model of chronic colitis

Totsuka, T., T. Kanai, K. Uraushihara, R. Iiyama, M. Yamazaki, H. Akiba, H. Yagita, K. Okumura, and M. Watanabe. Therapeutic effect of anti-OX40L and antiTNFMAbs in a murine model of chronic colitis. Am J Physiol Gastrointest Liver Physiol 284: G595–G603, 2003. First published January 10, 2003; 10.1152/ajpgi.00450. 2002.—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 antiOX40L 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-TNFMAbs to improve the therapeutic effect. Administration of antiOX40L 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 TNFproduction by lamina propria CD4 T cells. The combination with anti-TNFMAb further improved the therapeutic effect by abolishing IFN, IL-2, and TNFproduction 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 TNFblockade, may be a promising strategy for therapeutic intervention of Crohn’s disease.