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Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells.
J Immunol. 2009 Jun 15; 182(12):7440-50.JI

Abstract

Celiac disease is a chronic inflammatory enteropathy caused by cellular immunity to dietary gluten. More than 90% of patients carry HLA-DQ2 encoded by HLA-DQA1*05 and DQB1*02, and gluten-specific CD4(+) T cells from intestinal biopsies of these patients are HLA-DQ2-restricted, produce Th1 cytokines and preferentially recognize gluten peptides deamidated by tissue transglutaminase. We generated mice lacking murine MHC class II genes that are transgenic for human CD4 and the autoimmunity and celiac disease-associated HLA-DR3-DQ2 haplotype. Immunization with the alpha-gliadin 17-mer that incorporates the overlapping DQ2-alpha-I and DQ2-alpha-II epitopes immunodominant in human celiac disease generates peptide-specific HLA-DQ2-restricted CD4(+) T cells. When exposed to dietary gluten, naive or gliadin-primed mice do not develop pathology. Coincident introduction of dietary gluten and intestinal inflammation resulted in low-penetrance enteropathy and tissue transglutaminase-specific IgA. Two further strains of transgenic mice expressing HLA-DR3-DQ2 and human CD4, one with a NOD background and another TCR transgenic having over 90% of CD4(+) T cells specific for the DQ2-alpha-II epitope with a Th1 phenotype, were also healthy when consuming gluten. These humanized mouse models indicate that gluten ingestion can be tolerated without intestinal pathology even when HLA-DQ2-restricted CD4(+) T cell immunity to gluten is established, thereby implicating additional factors in controlling the penetrance of celiac disease.

Authors+Show Affiliations

Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19494267

Citation

de Kauwe, Andrea L., et al. "Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-transgenic Mice Expressing Specific Anti-gliadin CD4+ T Cells." Journal of Immunology (Baltimore, Md. : 1950), vol. 182, no. 12, 2009, pp. 7440-50.
de Kauwe AL, Chen Z, Anderson RP, et al. Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol. 2009;182(12):7440-50.
de Kauwe, A. L., Chen, Z., Anderson, R. P., Keech, C. L., Price, J. D., Wijburg, O., Jackson, D. C., Ladhams, J., Allison, J., & McCluskey, J. (2009). Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. Journal of Immunology (Baltimore, Md. : 1950), 182(12), 7440-50. https://doi.org/10.4049/jimmunol.0900233
de Kauwe AL, et al. Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-transgenic Mice Expressing Specific Anti-gliadin CD4+ T Cells. J Immunol. 2009 Jun 15;182(12):7440-50. PubMed PMID: 19494267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. AU - de Kauwe,Andrea L, AU - Chen,Zhenjun, AU - Anderson,Robert P, AU - Keech,Catherine L, AU - Price,Jason D, AU - Wijburg,Odilia, AU - Jackson,David C, AU - Ladhams,Jodi, AU - Allison,Janette, AU - McCluskey,James, PY - 2009/6/5/entrez PY - 2009/6/6/pubmed PY - 2009/6/26/medline SP - 7440 EP - 50 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 182 IS - 12 N2 - Celiac disease is a chronic inflammatory enteropathy caused by cellular immunity to dietary gluten. More than 90% of patients carry HLA-DQ2 encoded by HLA-DQA1*05 and DQB1*02, and gluten-specific CD4(+) T cells from intestinal biopsies of these patients are HLA-DQ2-restricted, produce Th1 cytokines and preferentially recognize gluten peptides deamidated by tissue transglutaminase. We generated mice lacking murine MHC class II genes that are transgenic for human CD4 and the autoimmunity and celiac disease-associated HLA-DR3-DQ2 haplotype. Immunization with the alpha-gliadin 17-mer that incorporates the overlapping DQ2-alpha-I and DQ2-alpha-II epitopes immunodominant in human celiac disease generates peptide-specific HLA-DQ2-restricted CD4(+) T cells. When exposed to dietary gluten, naive or gliadin-primed mice do not develop pathology. Coincident introduction of dietary gluten and intestinal inflammation resulted in low-penetrance enteropathy and tissue transglutaminase-specific IgA. Two further strains of transgenic mice expressing HLA-DR3-DQ2 and human CD4, one with a NOD background and another TCR transgenic having over 90% of CD4(+) T cells specific for the DQ2-alpha-II epitope with a Th1 phenotype, were also healthy when consuming gluten. These humanized mouse models indicate that gluten ingestion can be tolerated without intestinal pathology even when HLA-DQ2-restricted CD4(+) T cell immunity to gluten is established, thereby implicating additional factors in controlling the penetrance of celiac disease. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/19494267/Resistance_to_celiac_disease_in_humanized_HLA_DR3_DQ2_transgenic_mice_expressing_specific_anti_gliadin_CD4+_T_cells_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=19494267 DB - PRIME DP - Unbound Medicine ER -