Ortega Puente, Sara

Universitat Autònoma de Barcelona. Facultat de Veterinària

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Animal models of celiac disease.  Usefulness and limitations.  Author: Sara Ortega Puente*  *Grau de Veterinària 2011-2016; e-mail address: Sara.OrtegaP@e-campus.uab.cat June 2016 Celiac disease is a chronic enteropathy caused by inappropriate immune response against peptides of gluten present in dryland cereals, mainly affecting genetically predisposed individuals who express HLA-DQ2 and HLA-DQ8, although gluten is also able to activate innate immunity. The lack of an animal model that reproduces completely the disease  hinders the  progress  towards the  research on  the  CD   pathogenesis. Gluten intolerance  is  a  very  important  public  health  problem  because  it  is  clearly a disease underdiagnosed.  The aim  of  this literature review is to find the most suitable animal model in  order  to  clarify the disease pathogenesis process and to find new therapeutic targets.     Urgent need to develop safe and       therapeutic alternatives:  1. Use of  probiotics  and intestinal microbiota to  enhance  the   intestinal  permeability. 2. Promote the function of the intestinal barrier: some drugs act protecting the  integrity of the tight junctions in the small intestine. 3. Prevention  of  the  formation  of  immunogenic peptides: using polymers that bind to gliadin preventing recognition of MHC-II. 4. Oral enzyme therapy: the prolyl-endopeptidases (PEP) are able to easily  split  immunostimulatory  gluten  peptides  rich  in proline. Identifity a gluten threshold   dose well  tolerated by most patients   when    consuming  a PEP   specific dose. 5. Block the presentation of the peptide HLA.DQ. 6. Inhibitors of tissue transglutaminase (TG2) with activity limited towards the intestinal lining. 7. Blockade of gliadin transcellular transport. 8. Anti IL-15 and anti-IFN-γ  neutralizing antibodies are promising             candidates for future therapies. 9. NKG2D antagonists alters the growth and functions of reactive CD8+ T cells.  Figure 1. Immunopathogenesis of  MHC-II dependent CD.  The activation of T cells reactive  to  gluten in the small intestine triggers an inflammatory response dominated by Th1 cytokine profile, predominantly IFN- γ and other pro-inflammatory cytokines (TNF-α, IL-15)  with  proportional     decline of immunoregulatory cytokines (IL-10, TGF-β). This imbalance causes histological changes at the level of the intestinal wall .   Figure 2. Normal duodenal mucosa  of a  CD control patient (A) and a patient with CD (B) showing  villus atrophy and  hiperplasia of the crypts. (Arranz E et al. Inmunopatogenia de la enfermedad celiaca, 2012) Table 1.  Animal models for the study of gluten sensitivity: Usefulness and limitations. Gluten free-diet Transgenic animals are not the most appropriate model for CD, because they do not reflect reality. Instead, Macacus rhesus is  the most suited model for spon-taneous CD, but very few laboratories are approved by the ethics committee. New insights involving the swine SLA-II, particularly  mutations into the SLA-DQA and SLA-DQB, point out the possibility of a new CD model, but more research efforts would be needed to elucidate its suitability. Actually, there is no animal model so far that encompasses all the features in order to study the CD, but further studies are needed to find an effective therapeutic  strategy. 

Animal models of celiac disease. Usefulness and limitations

https://ddd.uab.cat/pub/tfg/2016/174580/TFG_sortegapuente_poster.pdf

Animal models of celiac disease. Usefulness and limitations

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