Protein identified that may play central role in inflammatory bowel disease

Researchers at the University of Virginia Health System have discovered that a protein expressed by the immune system, called TL1A, is linked to inflammatory bowel disease (IBD) in patients, especially Crohn’s disease. This is the first time TL1A has been linked to Crohn’s. In a study involving fifty patients at U.Va., published in the Nov. 1 issue of The Journal of Immunology, the research team found that TL1A was expressed in patients suffering from IBD, but not in control patients who are disease free. The finding could lead to new treatments for people who suffer from IBD, the general name for two diseases that cause inflammation in the intestines.

Ulcerative colitis causes inflammation and ulcers in the top layer of the intestinal lining, usually in the lower part of the large intestine, while in Crohn’s, the inflammation extends deep into the lining, usually in the small intestine. Over one million adults and children in the U.S. suffer from inflammatory bowel disease, with about 30,000 new cases diagnosed each year, according to the Crohn’s and Colitis Foundation of America. Adolescents and young adults are most susceptible to IBD and there is no cure.

“What we have discovered here at U.Va. is a cytokine, a key protein that regulates the immune response, that could be an important target for therapy in IBD patients who are not responding to current treatments for ulcerative colitis and Crohn’s disease,” said Dr. Fabio Cominelli, principal investigator of the study, professor of internal medicine and microbiology and director of the Digestive Health Center of Excellence at U.Va. “Blocking the interaction between TL1A and its receptor in the immune response, called DR3, could be beneficial to the thousands of people suffering from chronic intestinal inflammation.”

TL1A is a newly discovered member of the tumor necrosis factor (TNF) family of proteins thought to be expressed primarily in the endothelial cells that line the intestines. When TL1A interacts with DR3, found on active lymphocytes, the body can produce T cells as part of the inflammatory response associated with IBD. Anti-TNF drugs, such as Remicade®, are being used to treat people with moderate to severe Crohn’s symptoms that do not respond to conventional therapy.

Cominelli and his research team at U.Va. examined surgical specimens from patients with Crohn’s disease and ulcerative colitis, and from non-IBD control patients, who underwent therapeutic bowel resection. The researchers found minimal quantities of TL1A in the control specimens. But TL1A was present in the tissue of IBD patients and its expression correlated with the severity of inflammation. “The more inflammation present in a specimen, the more TL1A was found,” Cominelli said.

The researchers concluded that TL1A expression is significantly associated with Crohn’s disease, where the protein was found in large numbers in macrophage and lymphocyte cells of the gut immune system. The study found that, in contrast, TL1A was primarily found in the plasma cells of ulcerative colitis patients, pointing to the different physiologies of the two diseases. Interestingly, TL1A expression was not found in the intestinal lining of Crohn’s or ulcerative colitis patients.

Cominelli and his team at U.Va. are continuing their research into TL1A and other proteins that may play a role in inflammatory bowel disease. Earlier this year, they found that the monoclonal antibody against tumor necrosis factor (TNF) in the drug Remicade® protects intestinal cells from programmed cell death and promotes healing in damaged IBD tissue.