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. 2013 Jul 5:7:56.
doi: 10.1186/1752-0509-7-56.

Modeling of celiac disease immune response and the therapeutic effect of potential drugs

Oleg O Demin  1 , Sergey V Smirnov, Victor V Sokolov, Lourdes Cucurull-Sanchez, Cesar Pichardo-Almarza, M Victoria Flores, Neil Benson, Oleg V Demin
Affiliations

Modeling of celiac disease immune response and the therapeutic effect of potential drugs

Oleg O Demin et al. BMC Syst Biol. .

Abstract

Background: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD.

Results: A thorough analysis of the developed model provided the following results:1. TG-2 inhibitor treatment leads to insignificant decrease in antibody levels, and hence remains higher than in healthy individuals.2. TG-2 inhibitor treatment does not lead to any significant increase in villous area.3. The model predicts that the most effective treatment of CD would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APC. The model predicts that the treatment of CD 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.

Conclusions: The developed mathematical model of immune response in CD allows prediction of the efficacy of TG-2 inhibitors and other possible drugs for the treatment of CD: their influence on the intestinal villous area and on the antibody levels. The model also allows to understand what processes in the immune response have the strongest influence on the efficacy of different drugs. This model could be applied in the pharmaceutical R&D arena for the design of drugs against autoimmune small intestine disorders and on the design of their corresponding clinical trials.

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Figures

Figure 1
Figure 1
Network of processes of innate and adaptive immune responses described in the model. IEC activation (reaction #5), IEL activation (reaction #11) velocities are equal to zero and there are no differential equations for DQ2/DQ8 APC in the model for healthy subjects.
Figure 2
Figure 2
Decreasing of antibodies level after changing diet from gluten-containing to gluten-free.
Figure 3
Figure 3
Appearance of antibodies after changing diet from gluten-free to gluten-containing.
Figure 4
Figure 4
(a) Decreasing of antibodies level during treatment by different potential therapeutic agents; (b) Increasing of VA during treatment by different potential therapeutic agents (Curve for Permeability inhibitor coincides with curve for TG2 inhibitor).
Figure 5
Figure 5
Decreasing of antibodies level during TG-2 inhibitor treatment at different EC50 ratio.
See this image and copyright information in PMC

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