Lay Summary

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

One important and longstanding immunologic question is why pregnant women do not mount an immune response to their fetus.  Although the fetus is related to the mother, it is genetically distinct so that one would expect the mother to mount an immune response to attempt to reject the fetus, just as she would mount an immune response to reject an organ transplanted from a related, but not identical, individual.  A few years ago, other investigators demonstrated that the reason that a mother does not mount an immune response against her fetus is that there is a protein, indoleamine 2,3-dioxygenase (IDO), found in the placenta that suppresses the mother’s immune response against the fetus.

We have recently demonstrated that IDO is also found at high levels in the normal intestine and colon and at even higher levels in the inflamed intestine in colon of patients with inflammatory bowel disease.  We have also demonstrated that inhibition of IDO in a mouse model of colitis results in a dramatic worsening of the inflammation in the colon.

Just as the immune system in the uterus must be turned off so that it does not mount a response to the fetus, the immune system in the intestine must be turned off so that it does not mount an immune response to the bacteria that normally live in the intestine.  We believe that IDO is an important regulatory molecule in the intestine where its major function is to suppress the immune response to the bacteria in the intestine.  There is a considerable body of scientific evidence that suggest that the intestinal inflammation in IBD is a result of an inappropriate immune response to normal intestinal bacteria.  This raises two possibilities.  One is that a defect in the IDO system might lead to the inflammation seen in IBD.  The second possibility is that strengthening the IDO system might prevent intestinal inflammation.  One of the questions we would like to address in this study is whether further increasing levels of IDO prior to the induction of colitis would diminish the severity of the induced colitis in a mouse model.  If strengthening the IDO system in the mouse model prevents the development of colitis, that would suggest that strengthening the IDO system in patients with inflammatory bowel disease could prevent the development of subsequent disease flares.  A second question that will be addressed in this study is whether the levels of IDO activity in patients with inflammatory bowel disease correspond to the severity of the patient’s disease.  The demonstration of higher levels of IDO activity in patients with active IBD would suggest that IDO is a normal part of the protective mechanism against inflammation in inflammatory bowel disease.