Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), have identified a promising new target for autoimmune disease treatment – a cell-surface receptor called DR3. Their research in mice, published on line in the journal Immunity, suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do.

DR3 is a protein on the surface of cells. It is a member of the tumor necrosis factor (TNF) family of receptors, which bind to molecules related to TNF, a cell-signaling protein that promotes inflammation. Many of today’s most potent treatments for inflammatory diseases, such as rheumatoid arthritis and psoriasis, interfere with the action of TNF, thereby blocking inflammation. Since current anti-TNF therapies don’t work in all autoimmune diseases, however, the researchers turned to the study of DR3, which is a close relative of TNFR1, the main receptor for TNF.

Working with mouse models of asthma and multiple sclerosis, both immune system diseases, the researchers found that mice engineered to lack DR3 were resistant to those diseases. “The implication is that blocking DR3 in mice, and possibly in humans, is a potential therapy for these diseases and perhaps others in which the immune system goes awry,” said Richard Siegel, M.D., Ph.D., a scientist in the NIAMS’ Immunoregulation Group, who led the research effort.

While closely related to TNFR1, DR3 is expressed in T cells, a different kind of immune cell (a white blood cell that identifies and fights infection) than those that express TNFR1, Dr. Siegel said. The NIAMS group collaborated with a laboratory in Cardiff, Wales, which had generated genetically engineered mice deficient in DR3, as well as with a research group at the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which has developed mouse models of disease with strong T cell components, such as asthma and multiple sclerosis. “These findings open up new avenues for therapy of these two diseases as well as to other autoimmune diseases in which T cells play a role in causing or perpetuating the disease,” said Siegel.

The researchers hope that DR3-blocking agents will be effective anti-inflammatory treatments someday. Siegel noted that if they were to be used in rheumatic diseases, they would be a complement to strategies that block TNF because they hit a different arm of the immune system. “It could be potentially synergistic or complementary,” he said.

Of critical importance, the NIAMS scientists found that removing DR3 did not appear to suppress the immune response or the ability to fight infection within the mice – a problem with many other treatments for autoimmune disease. “We could see the effect of DR3 deficiency in the diseased organ, but when we looked systemically at the immune response at other places in the mouse, it was barely affected,” said Dr. Siegel. The group’s findings suggest that DR3-blocking agents might be more effective at specifically treating autoimmune disease without breaking down the body’s defenses against infections, a long-sought goal of researchers in the field.

Individuals who are obese are predisposed to a variety of metabolic conditions, including type 2 diabetes. A characteristic of the fat tissue (adipose tissue) of individuals who are obese is that it is inflammed, and understanding the relationship between such inflammation and the onset of the metabolic conditions is of importance in combating what has become a large public health problem. In a new mouse study, Gökhan Hotamisligil and colleagues, at the Harvard School of Public Health, Boston, found that interactions between adipocytes (fat cells) and inflammatory cells called macrophages seem to underlie the inflammation-related metabolic deterioration associated with obesity.

In the study, when adipocytes isolated from mice lacking proteins known as FABPs, which are molecules that govern metabolic and inflammatory responses, were cultured with normal macrophages, the macrophages expressed reduced levels of inflammatory molecules. Likewise, when macrophages isolated from mice lacking FABPs were cultured with normal adipocyes, the adipocytes responded more to insulin and took up more glucose. Similar results, indicating that FABPs from both adipocytes and macrophages contribute to the inflammatory basis for metabolic deterioration, were obtained in vivo. The authors therefore suggest that this FABP-related pathway may be a novel target for metabolism-related disorders.

The potentially fatal heart disease LQT-2, which is characterized by the prolongation of a specific interval of time (known as the QT interval) in the heart’s electrical cycle, is caused by mutations in the HERG gene. What triggers the changes in the electrical activity in the heart (and therefore in the beating of the heart) has not been completely determined, although loud noises and emotional stress can be triggers. In a new study, a team of researchers from the Academic Medical Centre, The Netherlands, and the University of Wisconsin, Madison, has revealed that fever can also trigger life-threatening changes in the electrical activity in the heart of patients with LQT-2.

The team, led by Arthur Wilde and Craig January, measured the electrical activity in the heart over time (something that is recorded in an ECG) of two LQT-2 patients with the same HERG mutation (A558P), and found that fever was associated with prolonged QT intervals in these individuals. When this mutation was introduced into a cultured human cell line, the cells exhibited temperature-dependent characteristics, including altered electrical currents across their cell membranes at high temperatures. The authors therefore conclude that similar changes in electrical currents occur in heart cells at the high temperatures associated with fever and that fever is a potential trigger of the potentially lethal changes in the electrical activity in the heart of patients with LQT-2.

A study from researchers at Children’s Hospital Boston published in Pediatrics found that a simple infection control intervention in elementary schools – disinfecting frequently-touched surfaces and using alcohol-based hand sanitizers – helped reduce illness-related student absenteeism.Illnesses caused by bacteria and viruses account for millions of lost school days each year.(1) According to Thomas Sandora, MD, MPH, a pediatric infectious diseases specialist at Children’s Hospital Boston, “The best ways to avoid common infections are cleaning your hands and preventing exposure to the germs that cause these illnesses. Our research indicates that elementary schools should consider a few simple infection control practices to help keep students healthier.”

The study, led by Dr. Sandora, was a randomized, controlled trial involving 285 third-, fourth-, and fifth-grade students in an elementary school system in Avon, Ohio. Teachers in intervention classrooms used disinfecting wipes on student desks, and students used hand sanitizer in the classroom at key points throughout the school day. Control classrooms followed usual hand washing and cleaning procedures.

Over eight weeks, researchers tracked the frequency of absences and the reasons for missing school. Study investigators also tested several classroom surfaces for total bacterial counts and for the presence of several common viruses.

Researchers found absenteeism rates for gastrointestinal illnesses were nine percent lower in classrooms that followed the infection control regimen of disinfecting surfaces and using alcohol-based hand sanitizers. The absenteeism rate for respiratory illness was not affected by this intervention.

Gastrointestinal illnesses are extremely common for school-age children, and children can be at risk for these infections because of frequent exposure to ill peers and poor hand hygiene.(1) In fact, the bacteria and viruses that cause these gastrointestinal infections can be easily passed from one person to another on the hands.(2) The germs can also survive on surfaces in the environment, where some of them can persist for hours to days.(1)

The study suggests that schools should consider adopting simple infection control practices, including disinfecting desktops once a day and using hand sanitizer before and after lunch, to help reduce days lost to common illnesses.

Different types of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin, appear to be equally effective in lowering the risk of Alzheimer’s disease, according to the largest study of its kind published in the May 28, 2008, online issue of Neurology®, the medical journal of the American Academy of Neurology. Experts have debated whether a certain group of NSAIDs that includes ibuprofen may be more beneficial than another group that includes naproxen and aspirin.Using information from six different studies, researchers examined data on NSAID use in 13,499 people without dementia. Over the course of these six studies, 820 participants developed Alzheimer’s disease.

Researchers found that people who used NSAIDs had 23 percent lower risk of developing Alzheimer’s disease compared to those who never used NSAIDs. The risk reduction did not appear to depend upon the type of NSAID taken.

“This is an interesting finding because it seems to challenge a current theory that the NSAID group which includes ibuprofen may work better in reducing a person’s risk of Alzheimer’s,” said study author Peter P. Zandi, PhD, with Johns Hopkins Bloomberg School of Public Health in Baltimore, MD. “The NSAID group that includes ibuprofen was thought to target a certain type of plaque in the brain found in Alzheimer’s patients. But our results suggest there may be other reasons why these drugs may reduce the risk of Alzheimer’s.”

The study’s lead author Chris Szekely, PhD, with Cedars Sinai Medical Center in Los Angeles, says the discrepancy between studies such as this one and the negative clinical trials of NSAIDs in treatment or prevention of Alzheimer’s need to be further explored.

Scientists search for drug candidates in some very unlikely places. Not only do they churn out synthetic compounds in industrial-scale laboratories, but they also scour coral reefs and scrape tree bark in the hope of stumbling upon an unsuspecting molecule that just might turn into next year’s big block buster. But one region that scientists have not been searching is their guts. Literally.Now, a team of researchers at Harvard Medical School, Brigham and Women’s Hospital, and the California Institute of Technology have demonstrated that a molecule produced by bacteria in the gut’s intestinal microflora can eliminate symptoms of inflammatory bowel disease (IBD), a condition that includes Crohn’s disease and ulcerative colitis, in animal models.

“Given the sheer number of bacteria in the gut, the potential for discovering new molecules that can treat a whole range of these diseases is promising,” says Dennis Kasper, co-lead author on the study, professor of medicine and microbiology and molecular genetics at Harvard Medical School, and director of the Channing Laboratory at Brigham and Women’s Hospital.

The study will appear as the cover story in the May 29 issue of Nature.

Scientists have known for many decades that the mammalian gut is an ecosystem teeming with approximately 1,000 different species of bacteria, species as distinct from the host as a single-cell amoeba in pond scum. Rather than causing disease, these bacteria are responsible for protecting against infection and aiding digestion. An increasing number of scientists also suspect that recent increases in asthma and even certain food allergies are caused by disruptions in the delicate balance of this intestinal ecosystem.

In 2005, Kasper and Sarkis Mazmanian, then a postdoc in Kasper’s lab and now an assistant professor of biology at the California Institute of Technology, discovered that a species of intestinal bacteria called Bacteroides fragilis could restore immune system balance in mice that were bred to lack intestinal bacteria. A particular product of B. fragilis, a sugar molecule called polysaccharide A (PSA), recovered the equilibrium of a certain subclass of immune system cells (called Th1 and Th2) whose levels became skewed when bacteria in the gut were absent. The researchers referred to PSA as a “symbiosis factor,” one that established a beneficial link between bacteria and mammals. This was the first study in which such a link was demonstrated.

Interestingly, when the study was completed, Kasper and Mazmanian found in these mice an abundance of immune system cells that were known to protect against colitis and Crohn’s disease. In the current report, the groups decided to expand these findings and explore potential links between PSA and inflammatory bowel disease.

When immunocompromised mice with a specific pathogen-free microbiota were given an intestinal bacterium called Helicobacter hepaticus, they soon developed “rip roaring” IBD, according to Kasper. However, when Helicobacter was combined with B. fragilis, the mice were fine. Further experiments revealed that PSA—the special sugar molecule—was the key factor in preventing IBD. In fact, when mice were given Helicobacter combined with PSA purified from B. fragilis bacteria, they showed no symptoms of IBD.

“But then the key question was, if PSA was essential for preventing these animals from coming down with either colitis or Crohn’s, how did it do it”” says Kasper. “What was the mechanism””

The answer came by studying a subset of interleukins, that is, molecules secreted by immune cells.

Previous studies had shown that two particular interleukins, called IL-17 and IL-23, promote intestinal inflammation and are present at high levels in IBD patients. Here, while the researchers found IL-17 and IL-23 in the guts of animals who had received Heliobacter alone, these interleukins were absent from animals who had also received both PSA-producing B. fragilis and purified PSA.

“We realized that something in PSA must be preventing the inflammation that causes colitis and Crohn’s, which would explain the reduction in IL-17 and IL-23,” says Kasper.

This hunch brought the researchers to consider a third interleukin, IL-10. The opposite of IL-17 and IL-23, IL-10 is anti-inflammatory and had previously been shown to protect against experimental colitis.

The researchers once again administered Helicobacter and PSA-active B. fragilis (the combination that had previously led to healthy mice), only this time they included an antibody that blocked IL-10. As a result, the mice all came down with IBD.

“This demonstrated for us the mechanism by which PSA protects against IBD,” says Kasper.

Indeed, the researchers deduced that PSA prompts immune system cells to secrete IL-10, which in turn suppresses the inflammation caused by IBD. In other words, PSA is an anti-inflammatory.

This research should encourage people (including many scientists) to consider the vast potential for beneficial contributions to human health by “good” bacteria. And what’s more, “This is the first time that a beneficial molecule produced by intestinal bacteria has been shown to work therapeutically in an animal model,” says Mazmanian.

The researchers caution that these findings do not promise any near-term treatments for IBD. “PSA might do the same thing in humans, and it might not,” says Kasper.

However, the mechanism that they’ve discovered should persuade scientists and drug manufacturers to consider new sources for expanding the drug pipeline.

“There is currently no effort to develop molecules that are naturally made by bacteria to use therapeutically,” continues Mazmanian. “This study opens up that possibility.”

Full citation:
Nature, May 29, 2008, 453 (7195), 620-624
“A microbial symbiosis factor prevents intestinal inflammatory disease”
Sarkis K. Mazmanian(1), June L. Round(1) & Dennis L. Kasper(2,3)