Prioritization of potential targets to evaluate the risks/benefits of the development of new drugs against celiac disease

Aim of the project:

To evaluate targets of possible drugs (transglutaminase-2 inhibitor, permeability inhibitor, IL-15 antibodies, IFN-y antibodies, DQ2-blocking peptides) on the basis of model-predicted efficacy for celiac disease treatment expressed in terms of clinically measured endpoints (villous area and antibody levels).

Results:

A systems pharmacology model of the immune response in celiac disease was developed. The model describes (1) the cell dynamics of intestinal epithelial cells, intraepithelial lymphocytes, T-cells, and antigen presenting cells (APCs); and (2) the influence of the cells and proteins that they produce on the deamidation of gluten peptides, change in villous area, and synthesis of antibodies. The model allows us to conclude that the most effective treatment for celiac disease would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APCs. The model predicts that the treatment of celiac disease by such gluten peptide analogs can lead to a decrease in antibody levels to those of normal healthy people and to a significant increase in villous area.

Initiator of the project:

Pfizer

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