Scientific Abstract

Proposal No.  IBD-0102
Principal Investigator:  Andrew T. Gewirtz, Ph.D.
Applicant Organization:  Emory University (Atlanta, Georgia, U.S.A.)
Project Title:  Adaptive immunity to flagellin in inflammatory bowel disease
Period of Award:  May 1, 2004 – April 30, 2006

The histopathologic hallmark of Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease (IBD), is the presence of increased numbers of leukocytes in the intestinal mucosa.  When analyzed during an acute flare of disease, these leukocytes are mostly innate immune cells, especially neutrophils, which are thought to cause the clinical manifestations of this disorder.  Conversely, histopathologic analysis of IBD patients performed during the chronic disease phase tends to show elevated numbers of lymphocytes, especially CD4 T-cells.

We have shown that the bacterial protein flagellin, the primary component of flagella, is a potent activator of innate immunity and may play a role in driving the active inflammation (i.e., neutrophil infiltration) associated with both acute infection and inflammatory bowel disease (IBD).  Furthermore, we have recently shown that, in mice, the innate immune response to flagellin can function as a link between innate and adaptive immunity, thus enabling flagellin to be a potent CD4 T-cell adjuvant.  We therefore hypothesize that flagellin may also play a role in driving the adaptive immune responses that maintain the chronic inflammation of IBD.  An effective and practical way of assessing adaptive immune responses in vivo in both humans and mice is by examining serum antibody titers.  Therefore, we propose to investigate our hypothesis by studying serum antibody titers to flagellin in a variety of human health and IBD, as well as in mice under well-defined experimental conditions.