A postdoctoral researcher in the immunology division at the Walter and Eliza Hall Institute, and a practising gastroenterologist, Dr Tye-Din believes he and former colleague Dr Bob Anderson may have found a means of eliminating coeliac disease. If clinical trials of the treatment are successful, the approach could also be applied to tackling other autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis. Almost as important, though, the discovery could improve the diagnosis of coeliac disease for the 80 per cent of Australians unaware they have it. He says undiagnosed coeliac disease is worrying because its effect on the small intestine means the body is less able to absorb nutrients, leading to loss of weight, fatigue or lack of energy and, in children, stunted growth. Coeliac disease is also associated with a range of even more serious problems such as liver disease, infertility, osteoporosis, other autoimmune disease and cancers such as lymphoma. People with undiagnosed coeliac disease have a two to fourfold higher rate of premature death. "The only treatment available at present is a gluten-free diet and that dates back to the 1950s when gluten was first identified as the cause of the disease. But it is not straightforward: the diet is tricky, you have to be ever vigilant, you have to pay more, put up with food that doesn't taste as good and often people don't always fully heal," Dr Tye-Din says. "Yet healing is critical because persistent damage in the gut is linked to long-term complications such as thinning of the bones and some forms of cancer. I've seen patients, even in their 20s, with bones like an 80-year-old, so people with the disease should have a bone density scan because of the risk of premature osteoporosis. Unfortunately, medical awareness and management of coeliac disease is far from optimal — meaning this doesn't always happen."

Gluten is a complex protein that enhances food texture. It allows bread to rise and imparts fluffiness, while gluten-free breads are heavy, crumbly, and far less tasty. Dr Tye-Din says the average Australian consumes 20-30 grams of gluten a day and the problem for coeliac sufferers is trying to ensure the foods they eat don't contain gluten when so many do — even Vegemite and liquorice. Yet consumption of tiny amounts of gluten as low as 50 milligrams, or a few crumbs from a slice of bread, can damage the small intestine. This fact, plus the complexity, cost and lifestyle restrictions of the gluten-free diet, spurred Dr Tye-Din and his colleagues to look for more effective treatments. "Coeliac disease has evolved from being a simple gut disorder that causes damage to the bowel and poor absorption of nutrients to being recognised as a primary immune condition with a multitude of manifestations — not just in the gut but also other organs. The knowledge certain genes are involved in the way the immune system reacts to gluten is also shaping our understanding. Such advances allow new approaches to be designed so as to improve on the gluten-free diet." Over a decade of tests on more than 300 patients with coeliac disease, the institute researchers discovered that key fragments of gluten — three "toxic peptides" — caused the abnormal immune response in people carrying the common coeliac-associated gene. These three peptides out of more than 18,000 in gluten are the ones, Dr Tye-Din says, "that tell the immune system to react badly to gluten". "Our approach was revolutionary in that it involved feeding people with gluten-containing food for three days and then taking samples of their blood on day six in hospital. That was when we found a lot of T cells — white blood cells — in the bloodstream reacting specifically to gluten. This showed us exactly which fragments were responsible for the immune response and provided a "road map" of what was toxic in coeliac disease."

The world's first therapy enabling coeliac disease patients to return to a normal diet would involve injecting them regularly with tiny quantities of the three peptides. The researchers believe the injections would induce an immune tolerance, allowing patients to again eat food made from wheat, barley or rye. "We showed that just three peptides were responsible for most of the immune response to gluten from all of the toxic cereals. Interestingly, the type of cereal consumed determined which gluten peptide was the most immunogenic," Dr Tye-Din says. "This allowed us to develop and test a peptide-based therapy, Nexvax2, which comprises these three peptides. Further development of the drug is now being led by a Boston-based company called ImmusanT, where Dr Bob Anderson has taken up the post as chief scientist." Discovery of the key peptides also means that improved diagnostic tests can be developed — a significant need given the poor rate of diagnosis in the community, he says. At present, people on a gluten-free diet have to go back to eating foods with gluten for up to eight weeks and then be tested to confirm they do have coeliac disease. In contrast, a new diagnostic test based on Nexvax2 would only need three days. "The first trial delivering injections of Nexvax2 to coeliac disease volunteers was completed in 2010 and showed it was safe and capable of inducing the predicted responses in the immune system. The critical next step will be to test whether Nexvax2 can prevent the adverse effects of dietary gluten and, depending on successful progress, it could be five or more years before a drug to counter coeliac disease is available," Dr Tye-Din says. "The approach of 'retraining' the immune system works in mouse models that have other human diseases, but for people with coeliac disease it will be a world first. If such an approach is effective this will have huge implications for the millions of sufferers globally."

He says similar immune-therapies could also be developed for other autoimmune diseases if the relevant disease causing triggers, or "antigens", could be as comprehensively defined as gluten has been — an ongoing challenge for researchers. *The Walter and Eliza Hall Institute and the national organisation Coeliac Australia have formed a three-year, $570,000 partnership to support research into new treatments and diagnostic tests for coeliac disease. The partnership aims to develop better treatments for children with the disease; effective responses to overcome symptoms after accidental gluten consumption; and a diagnostic test for coeliac disease in people with gluten intolerance who are following a gluten-free diet. Loading More information about the disease is available on the Coeliac Australia website at coeliac.org.au. The latest issue of The Australian Coeliac Magazine contains a detailed account by Dr Tye-Din of coeliac disease, its effects and the reasons why some people are susceptible. Information on the clinical trial can be found at immusant.com Read Geoff Maslen's blog atgeoffmaslen.edublog-s.org/