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Resistance to Celiac Disease in Humanized HLA-DR3-DQ2-Transgenic Mice Expressing Specific Anti-Gliadin CD4⁺ T Cells¹

Andrea L. de Kauwe^2,*, Zhenjun Chen^2,*, Robert P. Anderson, Catherine L. Keech^*, Jason D. Price^*, Odilia Wijburg^*, David C. Jackson^*, Jodi Ladhams^*, Janette Allison^* and James McCluskey^3,*

^* Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia; and Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute, Parkville, Australia

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 -gliadin 17-mer that incorporates the overlapping DQ2--I and DQ2--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--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a National Health and Medical Research Council of Australia Program Grant.

² A.L.d.K. and Z.C. contributed equally to the work.

³ Address correspondence and reprint requests to Prof. James McCluskey, Department of Microbiology and Immunology, University of Melbourne, Parkville 3010, Australia. E-mail address: jamesm1{at}unimelb.edu.au

⁴ Abbreviations used in this paper: CD, celiac disease; tTG, tissue transglutaminase; Tg, transgenic; hCD4, human CD4; mCD4, mouse CD4; TPO, thyroid peroxidase; MLN, mesenteric lymph node; MHCII, MHC class II; IEL, intraepithelial lymphocyte; B-LCL, B lymphoblastoid cell line.