Marie Curie Research Training Network
TRACKS
Transglutaminases: role in pathogenesis, diagnosis and therapy (TRACKS)
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Objective 4 : Obtaining a Transgenic Animal Model that allows the study of the Autoimmiune Response Found in Coeliac Disease
This objective will be achieved by the cloning of anti TG2 antibodies for cell transfection and intracellular targeting, in vivo expression by adenoviral vectors and production of transgenic mice. The purpose is the set-up of an experimental model for the study of the autoimmune response found in celiac disease.
Immunoglobulin gene sequences of intestinal B cell from celiac disease patients that encode for anti human TG2 antibodies will be cloned and identified by using phage-display approach. Antibody reacting to mouse TG2 and human TG2 with similar affinities will be selected and the sequences determining the antibody specificity will be grafted onto constructs of genomic mouse immunoglobulin genes that will then be used for microinjection and making of the transgenic experimental model.
This system will be integrated by HLA-DQ2 and gliadin reactive T cell receptor transgenic mice through a collaboration with Prof Lars Fugger, Oxford University, to provide a complete model system. All the antibodies required for the in vivo expression have already been cloned and characterised. In particular, human antibody fragments to TG2 were engineered by adding Fc antibody constant domains from man, rat and mouse. In preliminary experiments, these constructs have already been expressed in cultured cells as well as in mouse model by means of adeno-associated viral vectors.
