Courtesy of U.Va. Health System

Dr. Fabio Cominelli

Well-bred mice may hold clues to cause of Crohn's disease

By Matt Kelly

Mice with a naturally occurring bowel inflammation may lead U.Va. researchers to the cause of Crohn’s Disease.

Dr. Fabio Cominelli, director of the Health System’s Digestive Health Research Center, has been examining the mice as part of his effort to track down the cause of Crohn’s, a painful inflammatory bowel disease that affects about 1 million Americans.

Cominelli has recently detailed his research with mice in the March issue of the Journal of Clinical Investigation.

These particular mice, a genetically altered colony called SAMP1/Yit mice, originally came from Tokyo, where researchers found naturally-occurring lesions while they were researching a skin disease.

“They were sacrificing the animal when the doctors came across lesions that looked like Crohn’s Disease,” Cominelli said. “We have done a more elaborate analysis.”

Cominelli has been working with his colony of mice since 1996, performing additional breeding to sustain the population. He has bred the mice for 12 generations and he said they are now genetically different from the mice the Japanese are using.

Cominelli and his researchers worked on the mice for four years before they felt they had developed a reliable group. Researchers feared that by changing the mice’s environment, there was a risk that the predisposition to come down with intestinal lesions would be wiped out.

The mice are a particular benefit because Cominelli and his researchers can study them before they develop the disease, tracking changes and reactions as the disease progresses. Human subjects, on the other hand, can not be examined until they already have Crohn’s.

Researchers can also manipulate treatments, environment and genetic and microbiological conditions in ways that are not possible with humans.

“We can change the diet, use medications that are not approved for people, introduce ‘good’ bacteria into their systems,” Cominelli said. “We can do genetic manipulation, study the effect of the disease on the genes, transfer lymphocytes.”

Cominelli said the mice can be raised in a germ-free environment, then researchers can experiment by introducing different bacteria.

“These are remarkable mice because they respond to the same treatments as human patients,” Cominelli said.

Crohn’s patients receive a variety of medications to suppress the inflammatory response, permitting the tissue to heal, and to treat the symptoms, which include fever, diarrhea and abdominal pain.

The mice have generated a wealth of information for the researchers, including that the mice respond to antibiotics, Prednisone and other medications.

“We’re learning a fair amount of stuff,” Cominelli said, including which genes are involved in the process, the role lymphocytes or immune cells play in causing and mitigating the disease, the migration of cells in the disease process and which bacteria are helpful in finding a cure.

“We find great promise in what we have learned, because while there has been much progress in understanding some of the mechanisms involved in intestinal inflammation, using models developed through chemical or genetic manipulation, there remains a need of a model that displays the complexities specific to Crohn’s Disease,” Cominnelli said.

“A spontaneous model that can be used to further study Crohn’s disease in humans is significant. When combined with the remarkable resemblance of the mice lesions to human Crohn’s disease and similarities in associated immune responses, this model is a unique tool for pursuing the cause, and eventual cure, for this disease,” he added.

Cominelli received a $5.1 million, five-year grant from National Institutes of Health in September 2000 to study Crohn’s Disease. This funds the work of 25 people, including eight to 10 investigators, technicians, post-doctoral fellows and 1,000 to 1,500 mice, which cost about $100,000 a year to maintain.