MONDAY, Oct. 22, 2001 (HealthDayNews) -- Cutting a substance that's concentrated in the blood of people with a severe intestinal disorder may be a good target for future drugs, a new study on mice suggests.
Reducing levels of macrophage migration inhibitory factor (MIF) in mice can prevent or relieve murine colitis, the mouse equivalent of Crohn's disease, says an international team of researchers. Macrophages are immune cells that ingest infection-causing bacteria.
But the researchers caution that reducing the severity of Crohn's disease by reducing MIF levels may not lower the risk of colon cancer, which can be a long-term complication of the disease. The findings appear in the November issue of Nature Immunology.
Crohn's disease is an inflammatory disease of the gastrointestinal tract that causes diarrhea, cramping, rectal bleeding and loss of appetite. Like ulcerative colitis, it's classified as an inflammatory bowel disease (IBD). Roughly 1 million Americans suffer from IBD. The causes of the diseases are unknown, and there are no cures.
Senior investigator Cornelius Terhorst, chief of immunology at Beth Israel Deaconess Medical Center in Boston, says researchers decided to study MIF in detail when they discovered high levels of the substance in patients with active Crohn's disease.
Terhorst and his colleagues found that mice lacking MIF because of a genetic defect did not develop colitis, while introducing MIF triggered the disease.
In mice that already had colitis, the researchers found that introducing antibodies that block MIF reduced inflammation.
"During excessive inflammatory reaction, you have a lot of MIF, and in this model, it seems to be made by macrophages," says Terhorst. "That's part of the aggressive cascade [of inflammation]. If you now reduce MIF by two ways, either using the [genetic] knockout or by administering antibodies, then you seem to reduce that whole inflammatory cascade to a manageable situation."
Dr. Edward Boyko, professor of medicine at the University of Washington in Seattle, Wash., says while current Crohn's disease therapies are fairly effective, "none of these treatments directly addresses the cause of the colitis because the cause is not known. The treatment is aimed mainly at the signs and symptoms, and not at the cause."
"The agents that are used are non-specific inhibitors of inflammation," says Boyko. "There is an old one called sulfasalazine, and it has a close relative of aspirin as the active ingredient. It gets activated in the large intestine and decreases inflammation."
"Another way to treat colitis is by directly infusing the agent via the rectum, in an enema," he says. The therapy also uses a chemical relative of aspirin, along with corticosteroids, a class of medications that decrease inflammation and suppress the immune system.
Terhorst says because MIF is produced by the pituitary gland in the brain and may have other functions in the body, a molecule that inhibits MIF at the site of intestinal inflammation would be ideal.
Therapies used now don't work in about 35 percent of patients, says Dr. Maria Abreu, assistant director of the Inflammatory Bowel Disease Research Center at the Cedars-Sinai Health System in Los Angeles.
"What these investigators have done is test the idea that this particular chemical produced by the immune system, otherwise known as a cytokine,
is an important pro-inflammatory chemical," says Abreu.
"The most important part of the paper is that not only could they prevent disease by having animals that couldn't make this chemical, but that even in animals that had developed inflammation, they could give an antibody against the MIF and inhibit inflammation."
"This adds a very important potential therapeutic avenue to treat people with inflammatory bowel disease, but in particular, Crohn's disease," she says.
Boyko says the use of anti-inflammatories may be linked to a reduced risk of colon cancer in certain patients.
However, Terhorst says no data yet suggests that blocking MIF to reduce inflammation would reduce the overall risk of subsequent colon cancer.
What To Do: For more information on Crohn's disease and IBD, check the Web sites for the National Institute of Diabetes and Digestive and Kidney Disorders, the Crohn's and Colitis Foundation of America or the American Gastroenterological Association.
