Helminths and Immune Regulation
Joel Weinstock, MD, joined Tufts–New England Medical Center in 2005 as chief of the Division of Gastroenterology. He is also a professor of medicine at Tufts University School of Medicine and a member of the Immunology Program of the Sackler School of Graduate Biomedical Sciences. His clinical specialty is in inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Dr. Weinstock has active research programs in clinical studies of inflammatory bowel disease and in basic studies of the mechanisms of immune regulation. He is also one of the founders of a new research and treatment approach involving helminths (parasitic worms) and immune modulation.
Weinstock’s research on helminths may provide one explanation for the increase in immune disorders. Parasitic worms can live in the animal host’s gastrointestinal tract or bloodstream. To survive within the host, the worms must interact with and change the host’s immune system. “Almost everybody had worms up until the 20th century,” says Weinstock. “As a result of better hygiene – wearing shoes, sidewalks – children are growing up without the influence of worms.”
“The effects of worms on the immune system have been recognized by our and other labs for years. Many labs have considered these effects as potentially harmful and have worked to devise ways to get rid of worms. While some worms can cause disease, many are not harmful. So it occurred to us that the effects of worms on the immune system, the effects that regulate our immune systems, may not necessarily be harmful but could be beneficial.”
Weinstock’s research group is investigating the hypothesis that worms induce regulator pathways in the immune system that help prevent immunological diseases. “These diseases are spreading rapidly around the world, particularly in less developed countries as they industrialize and improve their standard of living,” says Weinstock. “Diseases like inflammatory bowel disease used to affect 1 in 10,000 people; it’s now becoming 1 in every 200 to 250 people. Something’s causing it, and it’s environmental.” Helminth research is part of a broader hygiene hypothesis that argues that better hygiene and a lack of exposure to microorganisms of various types during childhood have affected our immune systems, resulting in the development of immune disorders.
Studies are under way to dissect the cellular mechanisms influencing how worms interact with the host immune system. Using various model systems, Weinstock’s research group has shown that several types of worms regulate colitis by decreasing excessive inflammation. The mucosal immune system uses controlled inflammation to keep intestinal bacteria in the gut where they belong. “What we think is happening in some people is that the immune system starts seeing those organisms [gut bacteria] as more of a threat than it should, and it starts overreacting,” says Weinstock. This overreaction involves increased inflammation that causes the damage to the epithelium known as colitis.
“We think the worms are inducing regulatory molecules and regulatory cells that dampen both TH1 and TH2 pathways,” says Weinstock. TH1 and TH2 refer to two arms of the T lymphocyte helper cell pathways that regulate immune responses. “These regulatory cells tend to turn off adaptive immunity, a certain type of immunity that isn’t good in the gut. We demonstrated that worms induce the host to produce various regulatory immune cells. We’re in the process of determining which of these regulator-type cells could be critically important for protection of the intestine.”
Preliminary clinical studies of the pig whipworm to treat inflammatory bowel disease have had promising results. A biological agent has been licensed to two pharmaceutical companies that are developing it as a drug. After FDA clearance and European regulatory clearance, the drug will undergo clinical trials in the US and Europe. “The hope is that we’ll be able to do some of these clinical trials at Tufts–NEMC,” says Weinstock.
In addition to knowledge about the basic mechanisms of how helminths affect the immune system and treatment protocols for existing immune diseases, there is also a need to explore prevention of these disorders. “It is too soon to make recommendations for the average person’s lifestyle,” says Weinstock. “Our hypothesis is that we have to teach the immune system to behave properly. I suspect that modern-day life is training the immune system to be hyperreactive, which is leaving us prone to these diseases. Theoretically, if we’re correct, it may be possible to introduce, in a controlled way, transgenic [nonpathogenic] helminths into the gastrointestinal tracts of children, like you give polio vaccine, and in so doing modulate their immune systems so that when they’re 13 or 14 they’ll be less inclined to get allergies and other immune disregulation diseases.”
Weinstock is looking forward to collaborations with his new colleagues at Tufts University and Tufts–NEMC. “The GRASP (Gastroenterology Research on Absorptive and Secretory Processes) Center is ideal for the types of things that I’m doing,” he says. “The first thing we’re trying to set up is an understanding of how the worms communicate with the immune system.” While Weinstock is concentrating mostly on the gut, research has shown that worms can also regulate inflammation in the brain and the lung. “We had our first world congress on this topic back in May 2005, and we had scientists come together in Germany,” says Weinstock. “We called the meeting ‘Helminths and Immune Modulation.’ The group consists of parasitologists and immunologists and [involves] cross-fertilization among various models. People are addressing this area widely. If many of our observations are confirmed, if its importance to disease is confirmed, this is going to be a big area of study in the next ten years.”
For more information, please go to http://www.tufts.edu/sackler/immunology/weinstock/intro.html