New treatment for inflammatory bowel disease could soon enter clinical trials
Jane Bradbury

Immunostimulatory bacterial DNA sequences could provide a new treatment for inflammatory bowel disease (IBD), an international team of researchers suggests this week. Daniel Rachmilewitz (Shaare Zedek Medical Center, Jerusalem, Israel) and colleagues report that in three experimental and one spontaneous mouse model of colitis, administration of immunostimulatory bacterial DNA reduced colonic inflammation. In addition, the same DNAs inhibited in-vitro release of proinflammatory mediators from biopsy material from patients with either Crohn's disease or ulcerative colitis (Gastroenterology 2002; 122: 1428-41). "I think these data justify a speedy move into clinical studies", says senior researcher Eyal Raz (University of California, San Diego, CA, USA), adding that his Israeli colleagues are actively planning such trials. IBD comprises two related inflammatory disorders of the intestinal tract--Crohn's disease and ulcerative colitis. The exact cause of IBD remains unclear, but susceptibility genes and environmental factors have been implicated in its aetiology. Progress in the overall management of IBD is being made, but to date few innovative treatments have been described. In their search for such a new treatment, the researchers investigated the effects of small synthetic DNAs containing CpG motifs from bacterial genomes previously shown to have an immunostimulatory effect. "It was somewhat counterintuitive to try these molecules --ISS-ODNs [immunostimulatory oligonucleotides]--but we discovered that they had a strong anti-inflammatory effect in animal models for IBD", explains Raz. ISS-ODN was effective when injected or given orally, but a single dose did not provide long-term protection against colitis. "In clinical terms, this might mean that patients would need to take the drug orally every week or two", says Raz. "This is interesting work", comments Sander van Deventer (Academic Medical Center, Amsterdam, Netherlands), "and DNAs of this type have been used as immunostimulators in several diseases. But", he cautions, "there remain many unknowns in relation to the use of ISS-ODNs in IBD. For example, it is unclear which cells in the intestinal mucosa are stimulated by administration of ISS-ODNs." Raz agrees that it is unclear how immunostimulatory DNAs work in IBD but suggests that they could be both stimulating innate immunity and helping to protect the mucosal barrier. "ISS-ODNs could limit the invasion of commensal bacteria and/or their inflammatory products into the colonic mucosa and thus reduce mucosal inflammation. ISS-ODNs", he adds, "might actually work in an equivalent way to probiotics, which have been shown to be effective against colitis in clinical trials and could have the potential for providing a more controlled therapy for IBD".

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