LONDON – A better understanding of the molecular and cellular interactions that help to trigger inflammatory bowel disease in mice could one day lead to new ways of treating conditions such as ulcerative colitis and Crohn's disease in humans.

Recent investigations have shown that a molecule called T-bet plays an important part in keeping the gut healthy, by controlling the production of inflammatory cytokines.

Graham Lord, professor of medicine at King's College London, told BioWorld International: "We have shown that the transcription factor T-bet is the key molecular switch for controlling the production of the pathogenic cytokines that cause inflammatory bowel disease. We hope that, by targeting this molecule or its molecular pathways, we will be better able to treat this disease."

More effective treatments for inflammatory bowel diseases are urgently needed, he added, because those conditions affect millions of people worldwide and current therapies are toxic and not very effective.

In the normal gut, the immune system protects the body from infection by pathogenic bacteria, while at the same time tolerating the vast numbers of healthy bacteria that are normally present in the gut.

In people with inflammatory bowel disease, however, the immune system starts to attack the normal bowel flora, causing chronic inflammation.

Diseases such as Crohn's disease and ulcerative colitis can develop, which may need hospital treatment and surgery; patients frequently need to take medication throughout their lives to keep their symptoms under control. Many also develop colon cancer.

Lord and his collaborators have now established that T-bet is needed to prevent inflammation developing in the gut. The work is reported in the Oct. 12, 2012, issue of Immunity, in a paper titled, "The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor+ Innate Lymphoid Cells." The work was partly funded by the Wellcome Trust and the UK Medical Research Council.

When beginning the study, the team focused on a relatively newly described group of white blood cells that form part of the innate immune system: the innate lymphoid cells (ILCs). Over the past few years, studies had shown that those cells seem to be very important in driving autoimmune processes. In addition, ILCs were found to be present in animal models of colitis and in patients who had Crohn's disease and colitis.

Earlier work had also shown that genetically modified mice that lacked T-bet – so-called TRUC mice – spontaneously develop inflammatory bowel disease.

The UK team therefore set out to investigate the extent to which ILCs played a part in driving inflammation in TRUC mice, and to discover how the absence of T-bet was able to cause inflammatory bowel disease.

Their experiments showed that T-bet controls the ILCs, regulating their production of inflammatory cytokines. "We also identified that T-bet has this effect by regulating the interleukin-7 receptor, which is present on the surface of the ILCs," Lord added.

When the researchers blocked signaling by interleukin-7 in the TRUC mice, there was a dramatic fall in the numbers of ILCs found in the animals' intestines, and the animals' symptoms of colitis became less severe.

That finding is potentially therapeutically useful, Lord added. "Although it is not directly applicable to patients right now, because IL-7 is expressed on many other cells of the immune system in humans and, therefore, blocking it would no doubt have many side effects, it means that we may be able to find a way to target the ILCs through the pathway we have identified."

Future goals for the team include trying to identify a unique molecular signature for ILCs in humans in order to be able to target them with therapies.

"We want to find out more about the regulation of these molecular switches in ILCs and discover which molecules target them," Lord said. "In turn, this information will inform our models of inflammation and help us to work toward a viable therapeutic strategy for patients."

The strategy could be useful for any autoimmune inflammatory conditions, he added, including asthma.