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

Abstract

BackgroundCeliac 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.ResultsA 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.ConclusionsThe 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.

The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate

“…Several in vitro and in vivo studies indicate that paracellular permeability increases in CD. This increased permeability promotes the entrance of gliadin peptides into the lamina propria to trigger a potent adaptive immune response [Visser et al 2009; Demin et al 2013].…”

CYTOCON: The manually curated database of human in vivo cell and molecule concentrations

“…After developing a QSP model, the next step is to calibrate it, meaning to identify parameter values based on available experimental data 12,13 . A typical calibration workflow consists of several consecutive steps, including calibration against in vitro data, 13 baseline in vivo data, 7,9,14 and clinical data describing the response of a patient subpopulation to a particular treatment 7,9,12,15 .…”

“…After developing a QSP model, the next step is to calibrate it, meaning to identify parameter values based on available experimental data. 12,13 A typical calibration workflow consists of several consecutive steps, including calibration against in vitro data, 13 baseline in vivo data, 7,9,14 and clinical data describing the response of a patient subpopulation to a particular treatment. 7,9,12,15 To proceed with calibration against baseline in vivo data, you need to collect baseline values of cells and cytokines from the literature and implement them into the QSP model in terms of units introduced in your F I G U R E 2 Query and output interfaces.…”

Immunopathogenesis and therapeutic approaches in pediatric celiac disease

“…Thus, the use of tTG inhibitors could serve as a potential treatment option [108]. Many inhibitors have been developed in vitro [109], which includes competitive inhibitors (putrescine, cadaverine, fluoroscein), reversible inhibitors [110] and irreversible inhibitors (iodoacetamide, imidazolium derivatives) [111].…”