Protein may be target for Crohn’s therapy

October 31, 2001 at 1:12 pm

A protein called MIF–short for macrophage migration inhibitory factor–plays a central role in the process of inflammation. Researchers now report that MIF’s actions extend to the intestines. Their findings suggest that the protein perpetuates the chronic inflammation that characterizes Crohn’s disease, a painful gut disorder.

A view of macrophage migration inhibitory factor, a protein now implicated in Crohn’s disease. Lolis Lab/ Yale U. School of Medicine

In a series of experiments, the scientists induced mice to develop intestinal inflammation, or colitis. While not identical to Crohn’s disease in people, this mouse ailment closely mimics it, says study coauthor Cox Terhorst of Beth Israel Deaconess Medical Center in Boston. By giving mice antibodies to MIF, the researchers were able to prevent the disease from setting in and even reverse it in mice that already showed symptoms. The study appears in the November Nature Immunology.

While various cells make MIF, the researchers found that macrophages–a type of white blood cell–produced the MIF responsible for colitis. The scientists demonstrated this by stripping mice of their immune cells. They then injected into the bone marrow normal mouse stem cells that grew into various types of blood cells. Of these, macrophages were the main producers of MIF in inflamed intestinal tissue, Terhorst says.

To assess MIF’s role in people, the researchers tested blood samples taken from 18 Crohn’s patients and 7 people who are free of the disease. The people with Crohn’s disease had six times as much MIF in their blood as the healthy people did. After treatment with the drug infliximab, which blocks an inflammatory protein, blood concentrations of MIF fell sharply in the Crohn’s patients. This suggests that inhibiting that inflammatory protein can impede MIF secretion in the intestines.

“These results are very exciting,” says Thierry Calandra of the University Hospital in Lausanne, Switzerland. Some scientists hadn’t expected macrophages to play a major role in MIF-regulated inflammation, he says.

Previous work has indicated that MIF overrides normal immune signals aimed at stopping inflammation, he says. That makes MIF a potential target for drugs intended to treat Crohn’s disease.

Such drugs might include an antibody that attacks MIF or a small molecule that wedges into a nook in MIF’s molecular structure and thus inactivates it. However, Calandra notes, scientists have yet to find how MIF interacts with intestinal cells and still don’t know what positive role MIF might play in the body.