Generation and Validation of a New Humanized Mouse Model, A Surrogate for Human Celiac Disease

Developing and validating a humanized MISTRG6 mouse model that accurately replicates human immune responses to gluten for celiac disease research and drug development.
Completed Celiac Disease Gastrointestinal Diseases Adaptive Immunity Animal Models Biological & Mechanistic Experimental Platforms & Models Human Genetics T Cell Biology

Funding Year: 2023

Project Overview

Current mouse models of celiac disease fail to accurately replicate human immune responses to gluten, limiting their utility for research and therapy development. This project develops a humanized MISTRG6 mouse model incorporating key components of the human immune system — including HLA-B, HLA-DQ8, and HLA-E — alongside gluten-reactive transgenic T cells and human-derived chemokines that recruit cytotoxic T cells to the gut epithelium. Key advances include successful incorporation of HLA-DQ8 and HLA-E, identification of gluten-specific TCRs from patient CD8+ T cells, and optimized protocols for eliciting systemic gluten-specific immune responses. Oral challenge studies are underway to evaluate immune responses and disease progression in the refined model.

Impact & Innovation

A humanized mouse model purpose-built for celiac disease.

 

By integrating human HLA genetics, patient-derived chemokines, and gluten-reactive TCR transgenic T cells into a single MISTRG6 platform, this project creates the most human-relevant preclinical model for studying CeD pathogenesis and testing new therapies.

  • Incorporates HLA-DQ8, HLA-B, and HLA-E alongside gluten-reactive transgenic T cells to simulate human immune responses to gluten with unprecedented mechanistic accuracy
  • Generates commercial potential through MrGNewCo, a new company being formed to market the model to pharma, CROs, and animal purveyors as a premier platform for therapeutic testing and CeD diagnosis
  • Advances the Consortium’s Integrated Data and Discovery Platforms pillar by creating a shared, replicable humanized preclinical platform that can accelerate mechanistic discovery and therapeutic development across CeD research
Research Approach

A framework designed for discovery

This project combines genetic engineering of humanized mice, patient biopsy-derived molecular insights, and transgenic TCR methodology to develop and validate a MISTRG6-based mouse model that accurately replicates human immune responses in celiac disease. The work integrates model optimization with functional validation through oral challenge studies.

Genetic modification of MISTRG6 mice to incorporate HLA-B, HLA-DQ8, and HLA-E; identification and incorporation of patient biopsy-derived chemokines conducive to cytotoxic T cell recruitment; development of TCR transgenic mice harboring gluten-reactive T cells using known HER2 antigen and patient CD8+ T cell-derived gluten-specific TCRs; optimization of adjuvant protocols for systemic gluten-specific immune responses; and oral challenge studies to assess immune responses and disease progression.

Patient biopsy datasets identifying key chemokines and HLA components relevant to CeD pathogenesis, in vitro antigen presentation studies in collaboration with Drs. Jordan Pober and Marie Robert, TCR transgenic T cell characterization data, and oral challenge immune response and disease progression datasets from the optimized MISTRG6-CeD model.

Validation of the humanized MISTRG6-CeD model as an accurate surrogate for human celiac disease, enabling mechanistic studies and pre-clinical evaluation of therapeutics. The model is being commercialized through MrGNewCo to serve pharma, CROs, and research institutions as a premier platform for testing new therapeutic agents and advancing CeD diagnosis.

Investigators & Institutions

Powering the science

Principal Investigator

Richard Flavell, PhD, FRS, Colton Consortium Member

Sterling Professor, Department of Immunobiology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Publications

EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases

Nature Communications
Odell, AV; Newton, NM; Eisenstein, A; Micevic, G; Flavell, RA; Odell, ID October 2025
Animal ModelsBioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeDisease SubtypingExperimental Platforms & ModelsHuman CohortsMulti-omics IntegrationSingle Cell TechnologiesTherapeutic DevelopmentTranslational & ClinicalDermatologic DiseasesOtherSclerodermaSystemic DiseasesSystemic Sclerosis (Scleroderma)Yale University

Sclerotic GVHD and scleroderma share dysregulated gene expression that is ameliorated by EREG therapeutic antibody

Blood
Newton, NM; Agrawal, K; Odell, AV; Tracy, T; Hackett, C; Eldrup, A; Whitfield, M; Martyanov, V; Girardi, M; Sefik, E; Flavell, RA; Odell, ID December 2025
Animal ModelsBioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeDrug RepurposingExperimental Platforms & ModelsHuman CohortsMulti-omics IntegrationSingle Cell TechnologiesSpatial BiologyTherapeutic DevelopmentTranslational & ClinicalDermatologic DiseasesOtherSclerodermaSystemic DiseasesSystemic Sclerosis (Scleroderma)Yale University

T cell receptors for antigen on intraepithelial cytolytic T lymphocytes in celiac disease engage enterocyte HLA-E and HLA-B

Proceedings of the National Academy of Sciences
Johnson, JE; Agrawal, K; Al-Lamki, RS; Zhang, F; Wang, XD; Tobiasova, Z; Taleb, SA; Liburd, S; Rodriguez, L; Martins, AJ; Flavell, RA; Robert, ME; Sefik, E; Pober, JS February 2026
Adaptive ImmunityBioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeExperimental Platforms & ModelsHuman CohortsInnate ImmunitySingle Cell TechnologiesSpatial BiologyT Cell BiologyCeliac DiseaseGastrointestinal DiseasesYale University

The multiple roles of gamma interferon in intraepithelial T cell-villous enterocyte interactions in active celiac disease

bioRxiv [Preprint]
Johnson, JE; Agrawal, K; Al-Lamki, RS; Zhang, F; Wang, X; Liburd Jr, S; Tobiasova, Z; Rodriguez, L; Martins, AJ; Sefik, E; Flavell, RA; Robert, ME; Pober, JS September 2024
Adaptive ImmunityBiological & MechanisticCytokine SignalingExperimental Platforms & ModelsHuman CohortsIn Vitro ModelsInnate ImmunitySingle Cell TechnologiesT Cell BiologyCeliac DiseaseGastrointestinal DiseasesYale University

Additional Outputs

 Commercial development: MrGNewCo being formed to market the MISTRG6-CeD model to pharma, CROs, and animal purveyors.