Objective
Objectives:
Aims of the project: To use coeliac disease as a model for understanding the molecular basis of HLA association in disease. The main objectives are a) to elucidate, at a molecular level, the link between the HLA-DQ2 association and the immunopathological response to gliadin and b) to use this knowledge to investigate new treatment strategies
Background: HLA molecules are central to the function of the immune system. By presenting fragments of foreign and selfproteins to T cells, they regulate the immune responses of the body. The pivotal role of HLA in biomedical research has been underscored by the awarding of two separate Nobel prizes for research on HLA. The development of several chronic immunological disorders including insulin dependent diabetes mellitus, rheumatoid arthritis and coeliac disease depends both upon environmental and genetic factors. In these so-called HLA associated diseases, HLA genes are major genetic components. The rational design of effective prevention and therapy of HLA associated diseases requires a molecular understanding of how HLA molecules are involved in their pathogenesis. For many diseases this understanding is hampered by poorly defined HLA associations and unknown disease eliciting antigens. In this respect coeliac disease, an inflammatory mucosal disease, is an extraordinary exception. The HLA association (HLA-DQ2) is well defined and the disease eliciting antigen (wheat gliadin and related cereal proteins) has been identified.
In addition, HLA-DQ2 restricted, gliadin specific T cells have been isolated from the disease lesion of the gut, suggesting that these T cells playa role in the development of the disease. The actual gliadin derived peptides recognised by these T cells, however, still remain to be identified. Aims of the project: To use coeliac disease as a model for understanding the molecular basis of HLA association in disease.
The main objectives are: a) to elucidate, at a molecular level, the link between the HLA-DQ2 association and the immunopathological response to gliadin and b) to use this knowledge to investigate new treatment strategies. Methods and studies: We will identify the amino acid sequence of (possibly modified) gliadin derived peptides that are recognised by a panel of HLA-DQ2 restricted T cells of coeliac disease patients. A key element will be the testing of recombinant gliadins and fragments of natural gliadins for recognition by T cells isolated from the coeliac lesion.
To fulfil the second aim of the project, we aim to establish a transgenic mouse model for celiac disease. Mice will be made double transgenic for HLA-DQ2 and for a T cell receptor used by a gliadin reactive T cell of the coeliac lesion.
Benefits: HLA associated diseases are common chronic disorders which pose big challenges to European health care through the associated treatment costs and the impairment in life quality of affected individuals. The project aims to provide new insight into how HLA molecules are involved in the development of HLA associated diseases. Beyond advancing our scientific knowledge, the results from the project can facilitate the design of new effective measures for prevention and treatment of celiac.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences clinical medicine rheumatology
- medical and health sciences clinical medicine endocrinology diabetes
- medical and health sciences basic medicine immunology
- agricultural sciences agriculture, forestry, and fisheries agriculture grains and oilseeds cereals
- medical and health sciences clinical medicine gastroenterology
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Coordinator
0027 OSLO
Norway
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