Final Progress Report

Proposal No.   IBD-0070R
Principal Investigator:  William Stenson, M.D.
Applicant Organization:  Washington University (St. Louis, Missouri, U.S.A.)
Project Title: Indoleamine 2,3-dioxygenase in inflammatory bowel disease
Period of Award:  October 1, 2003 - September 30, 2005

Lay Summary:

Indoleamine 2,3-dyoxigenase (IDO) is an enzyme that acts as a natural brake on the immune response. This enzyme is found in the placenta and its actions block the ability of the mother’s lymphocytes to mount an immune response against the fetus. Thus is enzyme is at least in part responsible for the mothers ability to maintain her pregnancy without mounting an immune response against the fetus.

We found that IDO is also expressed in the intestine and acts to suppress the immune response there. In an animal model of colitis, TNBS colitis, we demonstrated that the expression of IDO is increased and that inhibition of IDO resulted in an increased severity of colitis. In the current study, we attempted to determine if increasing the expression of IDO prior to the development of colitis would diminish the severity of colitis. We address this question by administering CTLA-4Ig to mice prior to the induction of colitis with the administration of TNBS. CTLA-4 is a protein expressed on the surface of lymphocytes. CTLA-4 on lymphocytes binds to another protein B7 which is found on the surface of other immune cells including macrophages and dendritic cells.

A soluble form of CTLA-4, CTLA-4Ig, is known to induce the synthesis of IDO in macrophages and dendritic cells by binding to B7 on the surface of these cells. We administered CTLA-4Ig to mice and then induced colitis by the rectal administration of TNBS. We found that the administration of CTLA-4Ig resulted in the synthesis of IDO and a marked reduction of the severity of TNBS colitis as manifested by diminished mortality, diminished weight loss and diminished inflammation on histology. We were able to demonstrate that the beneficial effects of CTLA-4Ig on TNBS colitis were mediated through the induction of IDO by demonstrating that the simultaneous administration of CTLA-4Ig and 1mTH, an inhibitor of IDO, blocked the beneficial effects of CTLA-4Ig. The clinical implication of this study is that the administration of CTLA-4Ig or another agent that induces IDO expression in the intestine may be therapeutic in inflammatory bowel disease. Bristol Meyer Squibb is currently organizing a trial of CTLA-4Ig in human Crohn’s disease.