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Am J Physiol Gastrointest Liver Physiol 285: G754-G760, 2003; doi:10.1152/ajpgi.00071.2003
0193-1857/03 $5.00
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INFLAMMATION/IMMUNITY/MEDIATORS

Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis

N. Dan,1 T. Kanai,1 T. Totsuka,1 R. Iiyama,1 M. Yamazaki,1 T. Sawada,1 T. Miyata,1 H. Yagita,2 K. Okumura,2 and M. Watanabe1

1Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519; and 2Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.

Submitted 21 February 2003 ; accepted in final form 28 May 2003

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-{gamma} production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-{alpha} and IL-1{beta} production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.

Fas/FasL; murine model; Crohn's disease; therapy


Address for reprint requests and other correspondence: T. Kanai, Dept. of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8519, Japan (E-mail address: taka.gast{at}tmd.ac.jp).




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