Lay Summary

Proposal No.   IBD-0037
Principal Investigator:  Daniel Rachmilewitz, M.D.
Applicant Organization:  Shaare Zedek Medical Center (Jerusalem, Israel)
Project Title: Immunostimulatory DNA for the treatment of inflammatory bowel disease
Period of Award:  December 1, 2002 – November 30, 2004

Clinical and experimental evidence suggest that the cause of inflammatory bowel disease (IBD) is multifactorial involving both susceptibility genes and environmental factors.  There is also increasing evidence that bacteria play a critical role in the development of intestinal inflammation.

In recent years, bacterial DNA was shown to possess activating potential for the vertebrate immune system.  It has been shown that oligonucleotides containing CpG dinucleotides composed of an unmethylated cytosine (C) and guanine (G) are the immunostimulatory component of bacterial DNA.  These motifs that occur in bacterial DNA are rare in vertebrate DNA and are recognized by a specific Toll-like receptor – (TLR-9) present in vertebrate cells.  The anti-inflammatory and immunostimulatory properties of synthetic CpG motifs are currently being evaluated as monotherapies or as adjuvants with vaccines, allergens or antibodies in preclinical and clinical trials against cancers, viral and bacterial infections, allergies and asthma.  We have shown that they prevent or effectively decrease the severity of colitis in several animal models.

Since the current treatment of IBD is far from satisfactory, immunostimulatory oligonucleotides may be a novel effective treatment for IBD.  Prior to performing a clinical trial in IBD patients, we propose to:

• increase the understanding of the role of the receptor for bacterial DNA – TLR-9 in the intestinal tract;
• evaluate whether the beneficial effects of probiotic bacterial preparations in IBD are derived from its DNA;
• assess the effect of CpG motifs on the human colon; and
• identify the best CpG motif to be used in clinical trials in IBD patients.

The study will contribute to the understanding of the mechanisms involved in intestinal inflammation and will provide essential information before a novel therapeutic modality with synthetic oligonucleotides for IBD treatment is tried in humans.