# NIH grant: Organoid Modeling of Tissue-Resident Immunity in Celiac Disease (1R01AI198576-01) — retained record

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NIH grant 1R01AI198576-01: Organoid Modeling of Tissue-Resident Immunity in Celiac Disease
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: CALVIN J KUO. Award: $769846.
Start: 2026-08-01T00:00:00.
PROJECT SUMMARY
Celiac disease (CeD) is a prevalent and disabling autoimmunity in which dietary gluten exposure induces
intestinal epithelial destruction and associated symptomatology. The major risk factors for CeD are HLA-DQ2 or
HLA-DQ8, which directly present gluten-derived deamidated gliadin peptides to activate pathogenic CD4+ T cells
and induce cytotoxic CD8+ T cells to kill intestinal epithelium by poorly understood mechanisms. Studies of CeD
have been hampered by a lack of in vitro experimental models that preserve intestinal epithelium together with
endogenous tissue-resident immune populations without reconstitution. Although conventional organoids
propagate epithelium from CeD patients, immune components are notably absent.
 We have now created CeD air-liquid interface (ALI) organoids that robustly culture intact fragments
from CeD patient duodenal endoscopic biopsies and recapitulate gluten-induced pathology (Nature, 2024). The
resultant patient-derived CeD organoids co-preserve intestinal epithelium with tissue-resident T and B
lymphocytes, plasma cells, myeloid cells, and mesenchyme without any artificial reconstitution. Notably, gliadin
treatment of ALI CeD organoids induces epithelial death with gluten-specific T cell activation and expansion,
anti-TG2 autoantibody production and myeloid activation, none of which are present in non-CeD control subject
organoids. Our ALI CeD organoids also implicate IL-7 as a previously unsuspected and essential mediator of
gliadin-induced epithelial cell killing, as supported by IL-7 upregulation in clinical CeD biopsies.
 Here, we (PI Calvin Kuo and Co-Is Mark Davis, Nielsen Fernandez-Becker and António Santos)
exploit this holistic ALI CeD organoid method to explore mechanistic hypotheses of CeD pathogenesis. Aim 1
uses CeD organoids to test the hypothesis that gluten-induced anti-TG2 autoantibody production requires MHC-
II helper T cell stimulation and is IL-7-dependent, also addressing the unresolved question of whether CeD
autoantibodies are intrinsically pathogenic. Aim 2 employs CeD organoids to test the hypothesis that spatially
defined gluten-induced immune signaling hubs, via immune-immune and immune-epithelial interactions, mediate
epithelial killing and autoantibody production. This uses live multichannel confocal imaging, with spatial
transcriptomics and proteomics, to define cellular interaction mechanisms underlying CeD. Lastly, Aim 3
explores lamina propria fibroblasts as a novel cellular compartment in CeD pathogenesis that expresses IL-7 in
response to gluten, with IL-7 then being necessary and sufficient for gliadin-induced CeD organoid epithelial
killing. Here, we use scRNA-seq, organoid and cultured fibroblast approaches to explore the hypothesis that
gluten-stimulated T cells induce fibroblast IL-7 expression via cytokine and cellular interaction mechanisms,
Overall, we leverage synergistic team strengths and a novel human immunocompetent CeD organoid method to
functionally test hypotheses of gluten-induced autoimmunity, with basic and translational implications.
```



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