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  • Review Article
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Tolerance-inducing therapies in coeliac disease — mechanisms, progress and future directions

Subjects

Abstract

Coeliac disease is an autoinflammatory condition caused by immune reactions to cereal gluten proteins. Currently, the only available treatment for the condition is a lifelong avoidance of gluten proteins in the diet. There is an unmet need for alternative therapies. Coeliac disease has a strong association with certain HLA−DQ allotypes (DQ2.5, DQ2.2 and DQ8), and these disease-associated HLA-DQ molecules present deamidated gluten peptides to gluten-specific CD4+ T cells. The gluten-specific CD4+ T cells are the drivers of the immune reactions leading to coeliac disease. Once established, the clonotypes of gluten-specific CD4+ T cells persist for decades, explaining why patients must adhere to a gluten-free diet for life. Given the key pathogenic role of gluten-specific CD4+ T cells, tolerance-inducing therapies that target these T cells are attractive for treatment of the disorder. Lessons learned from coeliac disease might provide clues for treatment of other HLA-associated diseases for which the disease-driving antigens are unknown. Thus, intensive efforts have been and are currently implemented to bring an effective tolerance-inducing therapy for coeliac disease. This Review discusses mechanisms of the various approaches taken, summarizing the progress made, and highlights future directions in this field.

Key points

  • Coeliac disease is an autoinflammatory condition caused by hypersensitivity to cereal gluten proteins; gluten-specific CD4+ T cells drive immune reactions leading to an enteropathy and formation of autoantibodies.

  • Currently, the only available treatment is a lifelong gluten-free diet; there is an unmet need for treatment alternatives to this dietary intervention.

  • An antigen-specific therapy aiming to anergize, suppress or delete gluten-specific CD4+ T cells could be a way to treat the disease, such a tolerance-inducing therapy has the potential to become standalone therapy.

  • Various approaches for tolerance-inducing therapies have been designed and are pursued. These are currently in preclinical, phase I or phase II clinical development.

  • The molecular mechanisms involved in the tolerance-inducing therapies are not fully worked out.

  • How to best measure effectiveness of a coeliac disease therapy is debated; end points for phase III trials might not be the same as those used for phase II trials.

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Fig. 1: Immunobiology of the coeliac lesion in the small intestine and involvement of gut-associated lymphoid tissue for induction immune responses.
Fig. 2: Induction of regulatory T cells and establishment of bystander suppression.
Fig. 3: The liver with its special microenvironment promotes induction of immune tolerance.

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Acknowledgements

Work in the author’s laboratory is funded by grants from Stiftelsen KG Jebsen (project SKGJ- MED-017), the University of Oslo World-leading research program on human immunology (WL-IMMUNOLOGY), the Research Council of Norway (projects 333380, 324302, 295844, 287234) and the South-Eastern Norway Regional Health Authority (projects 2016113, 2018068, 2020027 and 2023075).

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Correspondence to Ludvig M. Sollid.

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During the past 3 years, the author has been a consultant for Bristol Myers Squibb, GSK, Mozart Therapeutics, Ono Pharmaceutical, Precigen ActoBio, Sanofi, SQZ Biotech, Takeda and Topas Therapeutics. He has also previously been a consultant for ImmusanT.

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Celiac Disease Foundation Therapy List: https://celiac.org/about-celiac-disease/future-therapies-for-celiac-disease

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Sollid, L.M. Tolerance-inducing therapies in coeliac disease — mechanisms, progress and future directions. Nat Rev Gastroenterol Hepatol 21, 335–347 (2024). https://doi.org/10.1038/s41575-024-00895-3

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