Poster Presentation International Celiac Disease Symposium 2026

Validation of TG2 Inhibition in a Humanized Mouse Model vs Patients Reveals Comparable Immune and Histologic Protection from Gluten Challenge in Celiac Disease (#251)

Aline Pesi 1 , Manuel Encalada 1 , Hicham El Mard 1 , Victor Zevallos 2 , Rambabu Surabattula 1 , Valeriia Dotsenko 3 , Ralf Mohrbacher 4 , Markku Mäki 5 , Keijo Viiri 5 6 , Elena F. Verdu 7 , Detlef Schuppan 1 8
  1. University Medicine Mainz, Mainz, RHEINLAND-PFALZ, Germany
  2. Karl-Landsteiner Universität für Ernährungswissenshaften, Krems, Austria
  3. Department of Virology, University of Helsinki, Helsinki, Finland
  4. Dr. Falk Pharma GmbH, Freiburg, Germany
  5. Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland
  6. Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
  7. Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
  8. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Background: Disease-specific therapies for celiac disease (CeD) require preclinical models with demonstrated human translational fidelity. We tested whether HLA-DQ8-transgenic NOD-DQ8 mice recapitulate histologic and mucosal immune effects of ZED1227, a selective oral transglutaminase-2 (TG2) inhibitor with clinical efficacy.

Methods: Intestinal TG2 target engagement was quantified by 5-biotinyl-pentylamine incorporation after poly-IC challenge. Gluten-sensitized NOD-DQ8 mice on a gluten containing diet received ZED1227 (25 or 50 mg/kg) or vehicle for the final 6 days (n=6/group); histology, immunohistochemistry, and duodenal RT-qPCR were assessed. Murine duodenal response signatures were then examined in subjects of the CEC-3 trial bulk RNA-seq (1,2; n=58 participants; 116 biopsies), using donor-balanced single-cell data, and MuSiC deconvolution.

Results: Oral ZED1227 markedly suppressed intestinal TG2 activity at 50 and 150 mg/kg (P≤0.0043 versus poly-IC/vehicle). Gluten-sensitized CeD mice developed reduced villus height-to-crypt depth ratio (VH:CrD) and increased CD3+ intraepithelial lymphocytes; both ZED1227 doses preserved VH:CrD and reduced CD3+ cells versus vehicle (all P<0.05). CD138+ plasma cells and additional CD45+, CD4+, and CD8+ inflammatory compartments were also significantly reduced. In the CEC-3 trial subjects ZED1227 induced a regulatory/adaptive transcriptional program spanning TGF-β/retinoid signaling, IL-10/FOXP3-associated regulation, SOCS2, and inhibitory E3-ubiquitin pathways. Six of nine murine response genes were robustly detected in human biopsies. A CBLB-CBLC-SOCS2 core score increased after ZED1227 versus placebo post-challenge (P<0.05) and correlated with VH:CrD (Spearman ρ=0.26, P=0.00424); the broader six-gene bridge module also correlated with VH:CrD (ρ=0.19, P=0.033). Independent single-cell mapping (3) localized bridge genes to lymphoid and regulatory compartments. Deconvolution identified treatment-associated immune shifts, while inferred plasma-cell abundance inversely correlated with VH:CrD (ρ=-0.48, P<0.0001).

Conclusions: TG2 inhibition produced concordant histologic and immune effects across humanized mice and patients. This cross-species alignment validates the refined NOD-DQ8 model as a translational platform for CeD drug development and identifies a conserved mucosal program linked to therapeutic protection.

  1. Schuppan D, Mäki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, Popp A, Koskenpato J, Langhorst J, Hovde Ø, Lähdeaho ML, Fusco S, Schumann M, Török HP, Kupcinskas J, Zopf Y, Lohse AW, Scheinin M, Kull K, Biedermann L, Byrnes V, Stallmach A, Jahnsen J, Zeitz J, Mohrbacher R, Greinwald R; CEC-3 Trial Group. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021 Jul 1;385(1):35-45. doi: 10.1056/NEJMoa2032441. PMID: 34192430.
  2. Dotsenko V, Tewes B, Hils M, Pasternack R, Isola J, Taavela J, Popp A, Sarin J, Huhtala H, Hiltunen P, Zimmermann T, Mohrbacher R, Greinwald R, Lundin KEA, Schuppan D, Mäki M, Viiri K; CEC-3 Investigators. Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease. Nat Immunol. 2024 Jul;25(7):1218-1230. doi: 10.1038/s41590-024-01867-0. Epub 2024 Jun 24. PMID: 38914866; PMCID: PMC11224021.
  3. FitzPatrick MEB, Antanaviciute A, Dunstan M, Künnapuu K, Trzupek D, Provine NM, Dooley K, Zhang JY, Irwin SL, Garner LC, Pernes JI, Ferreira RC, Sasson SC, Aschenbrenner D, Agarwal D, Rodrigues A, Howarth L, Brain O, Ruane D, Soilleux E, Teichmann SA, Dendrou CA, Simmons A, Uhlig HH, Todd JA, Klenerman P. Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. Nat Immunol. 2025 Jun;26(6):947-962. doi: 10.1038/s41590-025-02146-2. Epub 2025 May 6. PMID: 40328997; PMCID: PMC12133578.