IDO is an enzyme that metabolizes tryptophan resulting in depletion of tryptophan levels. Tryptophan depletion leads to an impairment of lymphocyte proliferation and a downregulation of the immune response. We have studied the role of IDO in regulating the inflammatory response in the intestine. IDO expression is induced in human inflammatory bowel disease and in the TNBS model of colitis in the mouse. Inhibition of IDO resulted in increased severity of TNBS colitis. In vivo administration of CTLA4-lg resulted in upregulation of IDO in the colon and in improved survival and diminished severity of inflammation in the TNBS model of colitis. The beneficial effects of CTLA4-lg in TNBS colitis were abrogated by the co-administration of an IDO inhibitor suggesting that the beneficial effects of CTLA4-lg were mediated through the induction of IDO. These findings have lead to the central hypothesis of this proposal which is: IDO is an important regulator of the inflammatory response in the intestine and upregulation of IDO expression has therapeutic potential in inflammatory bowel disease. To address this hypothesis we propose the following Specific Aims: 1) To define the mechanism by which IDO is upregulated in the TNBS model. Studies under this Specific Aim will include cellular localization of IDO using immunohistochemistry and flow cytometric cell sorting and definition of the roles of interferon alpha (IFNalpha) and interferon gamma (INFgamma) as mediators of IDO induction.2) To define the mechanism by which CTLA4-lg has a beneficial effect on the TNBS model. We have developed preliminary data demonstrating not only that administration of CTLA4-lg improves the TNBS model of colitis but also that the beneficial effects of CTLA4-lg are mediated through the induction of IDO. To further address the role of IDO induction in the beneficial effects of CTLA4-lg we propose to assess the affects of CTLA4-lg on TNBS colitis in the IDO knockout mouse. In addition we will determine if other agents that increase IDO expression also have beneficial effects in the TNBS model of colitis. 3) To determine if the beneficial effects that we have seen associated with increased IDO expression in the TNBS model of colitis extend to other models of intestinal inflammation, and in particular to the CD4+CD45RBhi transfer model of colitis. The long term goal of this project is to determine if there is a role for pharmacologic agents that increase IDO expression in the management of human inflammatory bowel disease.
| Thaker, Ameet I; Rao, M Suprada; Bishnupuri, Kumar S et al. (2013) IDO1 metabolites activate ?-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology 145:416-25.e1-4 |
| Gupta, Nitin K; Thaker, Ameet I; Kanuri, Navya et al. (2012) Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity. Inflamm Bowel Dis 18:1214-20 |
| Ciorba, Matthew A; Bettonville, Ellen E; McDonald, Keely G et al. (2010) Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis. J Immunol 184:3907-16 |
