Scientific Abstract

Proposal No.  IBD-0154R
Principal Investigator:  Giovanni Monteleone, M.D., Ph.D.
Applicant Organization:  University Tor Vergata of Rome (Italy)
Project Title:  Interleukin-21 triggers inflammatory signals in the gut.  Relevance for human inflammatory bowel diseases.
Period of Award:  July 1, 2005 – June 30, 2007

The etiology of inflammatory bowel disease (IBD) is unknown, but evidence has been accumulated to show that both Crohn’s disease (CD) and ulcerative colitis (UC) are caused by excessive immune reactivity in the gut wall.  Indeed, all treatment strategies for IBD patients are based on suppressing or modulating the immune system.  It appears that activated T cells play a central role in the pathogenesis of IBD, and that T cell-derived cytokines either directly or indirectly contribute to the intestinal tissue damage.     

We have recently shown that interleukin (IL)-21, a T cell-derived cytokine of the IL-2 family, is produced in excess at the site of disease in CD tissue.  Moreover, we showed that neutralization of IL-21 in CD lamina propria mononuclear cell cultures reduces Th cell type I signaling and interferon-gamma (IFN-γ) production, thus suggesting a role for IL-21 in the ongoing mucosal response in this disease.  High IL-21 was seen also in the inflamed areas of patients with UC, a disease that is not associated with a predominant Th1 cell response.  Based upon these observations, we hypothesized that IL-21 can trigger additional inflammatory pathways other than enhancing Th1 cell immunity in the gut.  Indeed, our preliminary data show that IL-21R is expressed by epithelial cells and myofibroblasts in the gut, and that both these cell types respond to IL-21.

This proposal is aimed at examining the role of IL-21 in IBD.  First, we plan to characterize the expression of IL-21R in the gut of patients with IBD, and examine whether IL-21R-induced signals regulate the production of chemokines and matrix metalloproteinases in epithelial cells and myofibroblasts respectively.  Second, we will examine whether IL-21 regulates T cell survival in the gut.  Finally, we will focus on murine models of T cell-dependent colitis, such as the Th1-associated TNBS-colitis and the Th2-dependent oxazolone-induced colitis, and analyze the expression of both IL-21 and IL-21R as well as the involvement of IL-21 in the induction/maintenance of the intestinal inflammation.

Results from the proposed experiments will shed light on the intestinal inflammation role of IL-21 in IBD and establish if blocking IL-21 activity reduces the severity of mucosal inflammation.  These studies will open new areas for therapy of IBD.