Important Lessons Derived from Animal Models of Celiac Disease (1)
Rats
Germ free Wistar AVN rats were used to study the effects of administering gliadin immediately after birth until 63 days old. Commensal bacteria affected the ability of gliadin to induce intestinal permeability.
Non-transgenic Mice
The in-bred line of Non- Obese Diabetic (NOD) mice demonstrated that they have a spontaneous sensitivity to gluten that does not require parenteral sensitization. The antibody response to tTG, which is clearly gluten dependent in celiac disease, was more related to the NOD strain and not gluten dependent.
Genetically Engineered Mice
CD4+ CD45RBlo CD25-cells were isolated from C57BL/6 mice that were sensitized to gliadin by injections of gliadin at the base of the tail and subsequently transferred to Rag1−/− mice on a gluten containing chow. The recipient Rag1−/− mice on a gluten containing chow developed histological features similar to those of celiac disease. DQ8 transgenic mice sensitized to gluten did not develop symptoms, they did develop a strong T cell proliferative response as well as antibody response with increased levels of anti gliadin IgG. In transgenic mice that express both HLADQ2 and HLADR3, sensitization to gliadin resulted in a strong T cell response to gliadin, but no overt enteropathy.
Interaction Between the Intestinal Microflora and Gluten
One powerful use of the mouse models is the ability to radically alter the intestinal microbial ecology through the administration of probiotics, pathogens, and even genetically altered organisms, as well as housing in a gnotobiotic facility, which would eliminate all microflora. E.coli and Staphylococcus were significantly more abundant in the duodenum of untreated pediatric celiac patients but that this returned to normal after the administration of a gluten free diet.
Testing of Novel Therapies Using Animal Models
Administration of EP-B2 to a gluten sensitive monkey during gluten challenge inhibited the development of symptoms; however it did have an increase in anti gliadin IgG and IgA and anti tTG IgG, even over the levels of other gluten-sensitive monkeys that had been regularly maintained on a gluten containing diet.
Important Lessons: Learned from the Animal Models Modeling pathogenesis
Gliadin binds to CXCR3, which is expressed by intestinal epithelial cells. The crosslinking of CXCR3 results in the release of zonulin (pre-haptoglobin-2), which causes the opening of the tight junctions between the epithelial cells. Both the transcellular and paracellular pathways were observed to occur in the gluten sensitive rhesus macaques.
Triggers of Celiac Disease
Repeated rotavirus infections during infancy may increase the risk of developing celiac disease. A subset of antibodies against tissue transglutaminase also binds to VP-7, a rotavirus protein. The introduction of gluten too early in an infant’s diet increases the risk for developing celiac disease. Breastfeeding can delay the onset of celiac disease.