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Latest in vitro and in vivo models of celiac disease.

ABSTRACT: Currently, the only treatment for celiac disease is a gluten-free diet, and there is an increased desire for alternative therapies. In vitro and in vivo models of celiac disease have been generated in order to better understand the pathogenesis of celiac disease, and this review will discuss these models as well as the testing of alternative therapies using these models.The research discussed describes the different in vitro and in vivo models of celiac disease that currently exist and how they have contributed to our understanding of how gluten can stimulate both innate and adaptive immune responses in celiac patients. We also provide a summary on the alternative therapies that have been tested with these models and discuss whether subsequent clinical trials were done based on these tests done with these models of celiac disease.Only a few of the alternative therapies that have been tested with animal models have gone on to clinical trials; however, those that did go on to clinical trial have provided promising results from a safety standpoint. Further trials are required to determine if some of these therapies may serve as an effective adjunct to a gluten-free diet to alleviate the adverse affects associated with accidental gluten exposure. A "magic-bullet" approach may not be the answer to celiac disease, but possibly a future cocktail of these different therapeutics may allow celiac patients to consume an unrestricted diet.

SUBMITTER: Stoven S

PROVIDER: S-EPMC3605231 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Latest in vitro and in vivo models of celiac disease.

Stoven Samantha S Murray Joseph A JA Marietta Eric V EV

Expert opinion on drug discovery 20130108 4

<h4>Introduction</h4>Currently, the only treatment for celiac disease is a gluten-free diet, and there is an increased desire for alternative therapies. In vitro and in vivo models of celiac disease have been generated in order to better understand the pathogenesis of celiac disease, and this review will discuss these models as well as the testing of alternative therapies using these models.<h4>Areas covered</h4>The research discussed describes the different in vitro and in vivo models of celiac ...[more]

PMID: 23293929

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Project description:Background & aimsCeliac disease could be treated, and potentially cured, by restoring T-cell tolerance to gliadin. We investigated the safety and efficacy of negatively charged 500-nm poly(lactide-co-glycolide) nanoparticles encapsulating gliadin protein (TIMP-GLIA) in 3 mouse models of celiac disease. Uptake of these nanoparticles by antigen-presenting cells was shown to induce immune tolerance in other animal models of autoimmune disease.MethodsWe performed studies with C57BL/6; RAG1-/- (C57BL/6); and HLA-DQ8, huCD4 transgenic Ab0 NOD mice. Mice were given 1 or 2 tail-vein injections of TIMP-GLIA or control nanoparticles. Some mice were given intradermal injections of gliadin in complete Freund's adjuvant (immunization) or of soluble gliadin or ovalbumin (ear challenge). RAG-/- mice were given intraperitoneal injections of CD4+CD62L-CD44hi T cells from gliadin-immunized C57BL/6 mice and were fed with an AIN-76A-based diet containing wheat gluten (oral challenge) or without gluten. Spleen or lymph node cells were analyzed in proliferation and cytokine secretion assays or by flow cytometry, RNA sequencing, or real-time quantitative polymerase chain reaction. Serum samples were analyzed by gliadin antibody enzyme-linked immunosorbent assay, and intestinal tissues were analyzed by histology. Human peripheral blood mononuclear cells, or immature dendritic cells derived from human peripheral blood mononuclear cells, were cultured in medium containing TIMP-GLIA, anti-CD3 antibody, or lipopolysaccharide (controls) and analyzed in proliferation and cytokine secretion assays or by flow cytometry. Whole blood or plasma from healthy volunteers was incubated with TIMP-GLIA, and hemolysis, platelet activation and aggregation, and complement activation or coagulation were analyzed.ResultsTIMP-GLIA did not increase markers of maturation on cultured human dendritic cells or induce activation of T cells from patients with active or treated celiac disease. In the delayed-type hypersensitivity (model 1), the HLA-DQ8 transgenic (model 2), and the gliadin memory T-cell enteropathy (model 3) models of celiac disease, intravenous injections of TIMP-GLIA significantly decreased gliadin-specific T-cell proliferation (in models 1 and 2), inflammatory cytokine secretion (in models 1, 2, and 3), circulating gliadin-specific IgG/IgG2c (in models 1 and 2), ear swelling (in model 1), gluten-dependent enteropathy (in model 3), and body weight loss (in model 3). In model 1, the effects were shown to be dose dependent. Splenocytes from HLA-DQ8 transgenic mice given TIMP-GLIA nanoparticles, but not control nanoparticles, had increased levels of FOXP3 and gene expression signatures associated with tolerance induction.ConclusionsIn mice with gliadin sensitivity, injection of TIMP-GLIA nanoparticles induced unresponsiveness to gliadin and reduced markers of inflammation and enteropathy. This strategy might be developed for the treatment of celiac disease.

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Latest in vitro and in vivo models of celiac disease.

Publications

Latest in vitro and in vivo models of celiac disease.

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