Scientists successfully treat new mouse model of inflammatory bowel disease

Researchers trying to improve cancer immune therapy have made an unexpected find: They've produced the most accurate mouse model to date of inflammatory bowel disease (IBD), a cluster of conditions that afflict approximately 1.4 million Americans with abdominal pain, constipation and diarrhea.

The two most common forms of IBD are Crohn's disease and ulcerative colitis (UC); in extreme cases, they can be fatal. The mouse model closely resembles the most serious form of human UC and is uniformly fatal. But scientists successfully treated the mice with a pair of broad-spectrum antibiotics, easing gut inflammation and increasing survival. The results, reported this week in Public Library of Science-Medicine, have researchers eager to follow up both in the clinic and the lab.

"The antibiotics we gave the mice were used individually in unsuccessful clinical trials as ulcerative colitis treatments, but now we have colleagues who are thinking of giving combined therapy an informal try," says co-senior author Thaddeus S. Stappenbeck, M.D., Ph.D., assistant professor of pathology and immunology and of developmental biology. "The antibiotics probably won't be a cure by themselves, but they may provide us with a potent new approach to combine with other therapies."

The mice may also allow scientists to learn which species of gut microorganisms are becoming embroiled in battles with host immune systems, triggering the symptoms of UC. That information could allow the development of stronger and more specific treatments.

Silvia Kang, a former graduate student in the laboratory of co-senior author Paul Allen, Ph.D., the Robert L. Kroc Professor of Pathology and Immunology, created the mouse model by crossbreeding two mouse lines they had developed for cancer immune therapy research. Each mouse line had one protein knocked out that restrained immune T cells from shifting into attack mode.

"The idea was to see if we could create super killer T cells we could use to attack tumors," says Allen. "But all the mice became sick early on, started to lose weight and we soon realized that they all had serious gastrointestinal issues."

Allen decided to consult with Stappenbeck, an expert in IBD.

"I've looked at quite a few proposed mouse models of IBD, and I recognized right away that this had the potential to be outstanding," says Stappenbeck. "The colons of the mice were incredible. They were filled with inflammatory T cells. We found the mice almost exactly replicated the most acute types of ulcerative colitis."

Unlike prior models of IBD, the mice consistently develop gastrointestinal problems within a short time period and at a predictable point in their lifespan. When researchers treated the mice at three weeks with the antibiotics ciprofloxacin and metronidazole, colon inflammation was reduced and the mice were able to gain weight and survive longer.

Scientists believe IBD results from the host immune system damaging the tissues of the gut while erroneously attacking food and gut microorganisms that aid food digestion. There are an estimated 500 different species of microbes living in the gut, so sorting out which species are being attacked by the immune system has been an imposing challenge.

The new model may significantly ease that challenge. Although the dual antibiotics used to treat the mice are broad-spectrum, they didn't sterilize the guts of the mice, suggesting that the treatment happened to eliminate the microorganisms causing IBD.

"We'd like to treat the mice and then reintroduce candidate microorganisms into their guts to see if this restarts the inflammatory reaction," says Stappenbeck.

Stappenbeck and Allen plan continued collaborative study of the model.

Source: Washington University in St. Louis

Related stories:

New study shows how T cell's machinery dials down autoimmunity
A St. Jude Children’s Research Hospital study shows that T cells, the body’s master immune regulators, do not use simple on/off switches to govern the cellular machinery that regulates their development and function. Rather, they possess sophisticated molecular controls that enable them to adjust their function with exquisite precision. Such subtle adjustment enables T cells to modulate their development and function, including avoiding autoimmunity.
Suspected cause of type 1 diabetes caught 'red-handed' for the first time
Scientists at Washington University School of Medicine in St. Louis working with diabetic mice have examined in unprecedented detail the immune cells long thought to be responsible for type 1 diabetes.
Researchers target tumors with tiny 'nanoworms'
Scientists at UC San Diego, UC Santa Barbara and MIT have developed nanometer-sized “nanoworms” that can cruise through the bloodstream without significant interference from the body’s immune defense system and—like tiny anti-cancer missiles—home in on tumors.
Researchers Link Master Regulator of Innate Immunity to the Hypoxic Response
Survival of all animals depends on their ability to withstand microbial infections and adapt to fluctuations in oxygen concentrations. These abilities depend on two ancient, evolutionary gene expression responses called the innate immune response and the hypoxic response.
Inflammation triggers cell fusions that could protect neurons
Chronic inflammation triggers bone marrow-derived blood cells to travel to the brain and fuse with a certain type of neuron up to 100 times more frequently than previously believed, according to a new study from the Stanford University School of Medicine.
Mature B cells reprogrammed to stem-cell-like state
Fully mature, differentiated B cells can be reprogrammed to an embryonic-stem-cell-like state, without the use of an egg according to a study published in the April 18 issue of Cell.
New strategies against bird flu
The Spanish flu outbreak of 1918 killed between 30 and 50 million people. In the infected patients, the ultimate cause of death was acute respiratory distress syndrome (ARDS). This fatal condition is a massive reaction of the body during which the lung becomes severely damaged. ARDS can be induced by various bacterial and viral infections, but also by chemical agents. These could be toxic gases that are inhaled or gastric acid when aspirated. Once ARDS has developed, survival rates drop dramatically. Among patients infected with H5N1 bird flu, about 50 percent die of ARDS.
Study sheds light on deadly lung disease
Systemic sclerosis (SSc), also known as scleroderma, is characterized by the formation of fibrosis, or scar tissue, on internal organs as well as the skin. Beyond its disfiguring symptoms, SSc is associated with a high rate of deadly lung disease. Pulmonary fibrosis strikes at least one-third of SSc sufferers, and kills 30 percent within 10 years. Assessing and treating SSc remains challenging, despite recent clinical trials, due in part to an incomplete understanding of the origins and progression of this autoimmune disorder.

News discussion:

Medicine & Health news