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

BMC Systems Biology

Oleg V Demin³  Neil Benson¹  M Victoria Flores⁵  Cesar Pichardo-Almarza⁴  Lourdes Cucurull-Sanchez²  Victor V Sokolov³  Sergey V Smirnov³  Oleg O Demin³ 

[1] Present affiliation: Xenologiq Ltd, Canterbury, UK;Present affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, UK;Institute for System Biology SPb, Moscow, Russia;Present affiliation: InScilico Ltd, London, UK;Present affiliation: eTherapeutics plc, Long Hanborough, UK

关键词: Immune response;    Drug development;    Gluten;    Mathematical modeling;    Celiac disease;   

Others  :  1142719
DOI  :  10.1186/1752-0509-7-56

 received in 2013-02-13, accepted in 2013-06-27,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Demin et al.; licensee BioMed Central Ltd.

【 图 表 】

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