Gut Instincts: What Harms Some Cells May Protect Against Inflammatory Bowel Disease

In a finding that could lead to improved treatment of chronic inflammatory bowel disease (IBD), Yale University researchers have uncovered a key mechanism in the immune system that appears to offer protection from the disorder. Their work appears in the December 19 issue of Immunity.

IBD is caused by an immune response gone awry. Detecting an inflammatory threat, T helper cells, which boost the body’s defense system, overreact. They secrete harmful proteins (cytokines) that destroy the lining of the gastrointestinal tract, causing further inflammation. The Yale team, led by Richard A. Flavell, chair of the Department of Immunobiology, found that the cytokine interleukin-22 (IL-22), which can damage tissue in diseases such as psoriasis, actually seems to play a protective role in the case of inflammatory bowel disease.

“It seems likely that this relates to the type of cell that responds to the IL-22 signal,” Flavell said. “Skin cells respond in an inflammatory manner and increase in number – that’s psoriasis. In the gut, however, the response to the IL-22 signal is to preserve the life of cells that would otherwise die. IL-22 switches on genes that keep cells alive. We don’t yet know why the reaction in the gut is different from that in the skin.”

Flavell’s team induced colitis in mice and found those that were deficient in interleukin-22 had more severe forms of the disease and higher mortality. In the mice that were protected by IL-22, researchers were surprised to find certain types of white blood cells of the immune system, commonly known as “natural killer cells,” acting in ways they had not been known to act.

“Natural killers cells were previously thought to play a role in fighting infection and tumors,” Flavell said. “Now, we can see that they also play a role in protecting host tissue from damage caused by an overreacting immune system.”

More than half a million Americans suffer from inflammatory bowel disease each year. The most common forms of IBD are Crohn’s disease and ulcerative colitis. Treatment most often consists of powerful anti-inflammatory drugs such as prednisone, which can weaken the body’s immune response. Severe cases may require bowel resection or permanent colostomy.

Yale scientist Lauren A. Zenewicz, first author of the paper, said the discovery of interleukin-22’s protective qualities could lead to treatment for IBD that avoids the side effects of current drug therapies, which can lead to increased susceptibility to disease.

According to Zenewicz, IL-22 only impacts tissues and has no direct effect on the immune response. “This specific targeting will allow us to modulate tissue responses to alleviate tissue destruction during inflammation, while having limited effects on the immune response itself.”

Before a new drug treatment based on IL-22 can become reality, however, Zenewicz cautions that more study is needed on its dual nature, to learn why it reacts differently in the context of different diseases. In addition, she said, researchers need to study the impact of a continuous course of IL-22 stimulation. “Gaining a better understanding of both the short-term and long-term effects of IL-22 on different tissues is needed to be able to develop IL-22-related therapeutics,” she said.

In addition to Zenewicz, Flavell’s team included George D. Yancopolous, David M. Valenzuela, Andrew J. Murphy and Sean Stevens, all of Regeneron Pharmaceuticals, Tarrytown, New York.

Citation: Immunity; Volume: 29; Issue: 6

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