‘Toxic trio’ in celiac disease pinpointed after analysis of 2,700 gluten peptides – Vaccine trial underway

“The holy grail in celiac disease research has been to identify the toxic peptide components of gluten; and that’s what we’ve done.”

Scientists in Australia and the UK have identified the three protein fragments that make gluten – the main protein in wheat, rye and barley – toxic to people with celiac disease.

Their discovery opens the way for a new generation of diagnostics, treatments, prevention strategies and food tests for the millions of people worldwide with celiac disease, with immunotherapy trials already underway.

When people with celiac disease eat products containing gluten their body’s immune response is switched on and the lining of the small intestine is damaged, hampering their ability to absorb nutrients. The disease is currently treated by permanently removing gluten from the patient’s diet.

Dr. Bob Anderson, head of the Walter and Eliza Hall Institute’s celiac disease research laboratory in Victoria, Australia, said it had been 60 years since gluten was discovered to be the environmental cause of celiac disease.

“In the years since, the holy grail in celiac disease research has been to identify the toxic peptide components of gluten; and that’s what we’ve done,” Dr Anderson said.

The research, done in collaboration with Dr. Jason Tye-Din, Dr. James Dromey, Dr. Stuart Mannering, Dr. Jessica Stewart and Dr. Tim Beissbarth from the institute as well as Professor Jamie Rossjohn at Monash University and Professor Jim McCluskey at the University of Melbourne, was published July 21 in the international journal Science Translational Medicine.

The study was started by Professor Anderson nine years ago and has involved researchers in Australia and the UK as well as more than 200 celiac disease patients.

The patients, recruited through the Celiac Society of Victoria and the Celiac Clinic at John Radcliffe Hospital, UK, ate bread, rye muffins or boiled barley. Six days later, blood samples were taken to measure the strength of the patients’ immune responses to 2,700 different gluten fragments. The responses identified 90 fragments as causing some level of immune reaction, but three gluten fragments (peptides) were revealed as being particularly toxic.

“These three components account for the majority of the immune response to gluten that is observed in people with celiac disease,” Dr. Anderson said.

This knowledge has already been used by Melbourne-based biotech company, Nexpep Pty Ltd, to develop a ‘peptide-based’ immunotherapy that aims to desensitize people with celiac disease to the toxic effects of gluten. Nexpep’s Phase 1 trials of the therapy were completed in June and final results are expected in coming months.

The immunotherapy works by exposing people with celiac disease to small amounts of the three toxic peptides and is based upon the same principles as desensitization for allergies.

Dr Anderson said that although celiac disease could be managed with a gluten-free diet, compliance with the diet is often challenging, and nearly half the people on the diet still have residual damage to their small intestine. “Consequently, the immunotherapy and three other drugs are under development to help people with celiac disease.”

Source: Walter and Eliza Hall Institute press release, Jul 21, 2010

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