Coeliac Disease
Development of a vaccine for coeliac disease
JA Tye-Din, J Stewart, JA Dromey, RP Anderson.
Coeliac disease (CD) is a lifelong immune disease caused by ingesting gluten derived from wheat, rye, barley and sometimes oats, affecting around 1% of Australian, European, American, Middle Eastern, West and South Asian populations. CD can be associated with a diverse range of clinical presentations and significant medical complications such as malnutrition, osteoporosis, infertility, liver failure and cancer. A gluten free diet is the only treatment but is expensive and difficult to comply with. In patients with CD, daily consumption of 50mg of gluten, equivalent to that contained in a 1/100th of a slice of standard wheat bread, damages the small intestine.
Many of the drugs under development for CD are likely to supplement the gluten free diet and simply provide a safeguard against inadvertent gluten exposure. Long-acting agents that qualitatively change the immune response to gluten, such as peptide-based therapeutic vaccines, are likely to replace the gluten free diet if they prove efficacious. In 95% of cases, CD is associated with a gene encoding HLA-DQ2, with the remaining 5% associated with HLA-DQ8. We have developed a peptide-based therapeutic vaccine for HLA-DQ2+ CD based on “immuno-dominant” T cell epitopes of gluten: regions of gluten that trigger vigorous T cell responses in the majority of people with the disease.
Whole antigen immunotherapy provides long-term remission in allergic diseases such as hay-fever, while a prototype vaccine using allergen (Fel-d1)-derived peptides recognised by CD4+ T cells in cat-sensitive asthma shows efficacy in Phase II clinical trials. In common with traditional whole antigen immunotherapy, peptide-based therapeutic vaccines delivered in multiple small doses over a course of injections or mucosal applications can induce immune tolerance not only to the selected immuno-dominant epitopes or protein but also potentially spreading to involve other sub-dominant pathogenic epitopes.
A comprehensive pre-clinical program has been successfully completed and we are now finalising preparations for a Phase Ib clinical trial in Melbourne in late 2008.
Dr Bob Anderson with a vial of the therapeutic peptide vaccine he and his team have developed for coeliac disease. It is ready to be tested in clinical trials.
People, porridge, and peptides: avenin toxicity in coeliac disease
JA Stewart, F Schmitz, J Tye-Din, RP Anderson
Depending upon the country in which you live, oats might be excluded from a gluten free diet for the treatment of coeliac disease (CD). Evidence to support the oat debate in CD is weak, and there are no clinical tests to guide individual dietary recommendations. We have explored the immunology of oats in CD by assessing the T cell stimulatory activity of gluten-like proteins in oats (avenins). Half of coeliac volunteers have T cells specific for avenin peptides after oat challenge but not before. Immunity to oats is common in CD. A diagnostic test based on these findings appears feasible.