Coeliac disease - a food induced disorder. exploration and exploitation of t cell stimulatory gluten peptides.

Projektinformationen

GLUTEN EPITOPES IN C

ID Finanzhilfevereinbarung: QLK1-CT-2000-00657

Projekt abgeschlossen

Startdatum 1 Januar 2001

Enddatum 31 Juli 2004

Finanziert unter

• Specific Programme for research, technological development and demonstration on "Quality of life and management of living resources", 1998-2002

Gesamtkosten € 1 092 072,00

EU-Beitrag € 1 092 072,00

Koordiniert durch

UNIVERSITY OF OSLO
Norwegen

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Leistungen

Development of a humanized mouse model for celiac disease

A transgenic mouse line expressing the HLA-DQ2 and a human gamma-gliadin specific T cell receptor was established. Disease-induction experiments led to the result that gluten strongly induces tolerance in the mice (not yet published). The gluten-induced tolerance can be broken by administration of high levels of interleukins or purified anti-IL10mAb.

Definition of barley, rye and oats derived epitopes that are causative for coeliac disease

The sequence of peptides of barley (hordeins), rye (secalins) and oats (avenins) which are recognise by HLA-DQ2 restricted intestinal T cells of coeliac disease patients have been determined. Some T cells demonstrate cross-reactivity against peptides of different cereals whereas other T cells are specific for certain peptides. In particular the T cell responses to oats avenin are clinically relevant. Oats avenin are generally considered safe for coeliac disease patients. Our results however demonstrate that there exist peptides of oats, which are recognised by intestinal T cells of celiac disease patients. In addition, we have demonstrated some cases of coeliac disease patients who have clinical oat intolerance, mucosal inflammation related to oats ingestion and intestinal T cells reactive with oats avenin peptides. It thus appears that some (few?) coeliac disease patients develop oats intolerance and we advice that celiac disease patients who are consuming oats should receive clinical follow-up.

Development of a prototype testkit for detection of gluten and gluten-like epitopes in food

The aim of this part of the project was to develop a sensitive method to detect T cell stimulatory epitopes of the N-gliadin and x-gliadin molecules in food products. For this purpose nonoclonal antibodies (mAb) were raised against peptides encoding the T cell stimulatory epitopes of N-gliadin (aminoacids, aa 59-71), and x-gliadin (aa 142-153 and aa 147-159). With these mAb competition assays were developed that quantitatively detected gluten derived T cell stimulatory epitopes present on both intact proteins and peptides of sizes recognizable by CD4+ T cells. Moreover, the presence of T cell stimulatory epitopes could also be detected in preparations of barley, rye and triticale, other cereals known to be toxic for coeliac disease patients. This method can now be used to further ensure the safety of food consumed by patients with coeliac disease.

Characterisation of adult and pediatric T cell responses to the gluten and gluten like epitopes in wheat, barley, rye and oats

Intestinal T cell responses in number of children and adults to T cell epitopes in wheat gluten, and gluten like epitopes in wheat, barley, rye and oats have been examined. The results demonstrate that there are T cell responses to a number of epitopes both in children and adults, but also that there exists a hierarchy with respect to how frequently the epitopes are recognised. Almost all patients have intestinal T cells reactive to some T cell epitopes of alpha-gliadin in wheat whereas responses to most other epitopes are more variable. Although there exist some peptides that are recognised in their native sequence, most epitopes are only or better recognising when certain glutamine residues have been converted to glutamate (i.e. deamidation).

Definition of gluten derived T cell epitopes that are causative for coeliac disease

The work of this project has lead to a detailed characterisation of cereal peptides, which are recognised, by intestinal T cells of coeliac disease patients. The results demonstrate that the responses are diverse, but that there is a hierarchy as to how frequently the various epitopes are recognised. The collective results demonstrate that T cell stimulatory peptides are present in the gliadin as well as the LMW and HMW-glutenins. These results have important implications for advice on food safety to patients. Gliadin-DQ2 tetramer reagents that allow staining of antigen specific T cells have been developed. Gliadin-DQ2 tetramer reagents allow for specific detection of antigen reactive T cells and potentially be utilised as a diagnostic adjunct to detect gluten reactive T cells in the peripheral blood after oral challenge with gluten.