Scientific Abstract

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

Impaired mucosal barrier, cytokine imbalance and dysregulated CD4⁺T cells play important roles in the pathogenesis of inflammatory bowel disease (IBD).  Immunostimulatory DNA sequences and their synthetic analogs (ISS ODNs) are unmethylated CpG dinucleotides common in bacterial and viral genomes.  ISS ODNs induce secretion of the Th-1 cytokines; upregulate cell surface molecules; elicit mucosal and Th-1 immunities; enhance hosts’ defense against pathogens; and rescue cells from death.  We have recently found that ISS-ODN prevent or significantly ameliorate the severity of colonic inflammation in four models of murine colitis.  The beneficial effects of probiotics in IBD patients and also in models of colitis may be derived from the genomic DNA of these bacteria as well.  The cell survival properties of ISS-DNA, together with the immunostimulatory effect on innate immunity, most likely limit invasion of commensal bacteria and/or other products into the colonic mucosa and therefore may be a novel therapeutic modality in IBD patients.

In preparation for a clinical trial with ISS ODNs for IBD treatment, the aim of the present study is:

   1.    To determine whether the beneficial effects of probiotics are derived from their DNA sequences.
      
   2.    To determine the effect of ISS-ODN on the generation of proinflammatory cytokines by human colonic mucosa.
      
   3.    To screen several ISS ODNs for their effect on human colonic cytokine generation in order to identify the most potent ODN to be used in clinical trials.

These studies will generate novel insights into the physiologic functions of TLR-9 in the intestine, will clarify the mechanism of action of probiotics, will demonstrate the effect of ISS ODNs on the human colon and will identify the best ISS-ODN to be used in clinical trials in IBD.