A Systematic Review of Regulatory T Cells and Transglutaminase 2 Inhibitors in Celiac Disease

Celiac.com 11/05/2025 - Celiac disease is an immune condition in which eating gluten sets off inflammation that harms the lining of the small intestine. The current standard of care is a strict gluten-free diet, but many people still experience symptoms or worry about accidental exposure. This systematic review examined two emerging treatment ideas that act directly on the immune system: medicines that block an enzyme called transglutaminase 2, and approaches that boost or restore the calming arm of the immune system through cells known as regulatory T cells. The goal was to see whether these strategies can lessen damage in the gut, reduce symptoms, and improve everyday health.

Why These Two Targets Matter

Transglutaminase 2 helps the body repair tissue, but in celiac disease it changes parts of gluten in ways that make them more likely to be seen as dangerous by the immune system. This sets off a chain reaction that injures the intestinal surface and causes ongoing inflammation. Blocking transglutaminase 2 may interrupt that chain reaction at its source.

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Regulatory T cells are the immune system’s built-in brakes. They tone down overreactions and help the body tolerate harmless exposures, such as food proteins. If regulatory T cells are too few or do not work well, inflammation can spiral out of control. Strengthening their number or function could restore balance and protect the gut.

How the Review Was Performed

The authors searched major medical databases for full-text studies published in English during the past two decades and screened them for quality. Fourteen studies met the criteria and were analyzed. The studies included controlled human trials of transglutaminase 2 blockers, laboratory work using human biopsies and cell lines, and investigations of regulatory T cells in people with celiac disease who were exposed to gluten in a controlled way.

What the Studies Showed about Transglutaminase 2 Blockers

Multiple clinical trials tested an oral medicine that inhibits transglutaminase 2 during a short, supervised period of gluten exposure. Across dose ranges, people taking the inhibitor had less injury to the small intestinal lining than those taking a placebo. Measures that reflect intestinal health, such as the ratio of villus height to crypt depth, were better preserved. Counts of inflammatory cells within the lining of the intestine were lower, and participants reported fewer symptoms at the higher dose. Several studies also showed that the medicine localized to the intestinal brush border, the area most affected in celiac disease, which supports the idea that it is acting where it is needed.

Laboratory and ex vivo experiments reinforced these findings. When intestinal cells and celiac disease biopsies were exposed to fragments of gluten, adding transglutaminase 2 inhibitors reduced barrier disruption, lowered inflammatory signals, and limited harmful changes in cell structure. Together, these results suggest that blocking the enzyme can both protect the gut lining and quiet the inflammatory cascade that follows gluten exposure.

What the Studies Showed about Regulatory T Cells

Research on regulatory T cells found two main patterns. First, people with celiac disease often have regulatory T cells present, but those cells may not suppress inflammation as effectively as they should. Second, when researchers stimulated regulatory pathways in tissue from people with celiac disease, the inflammatory response to gluten decreased. For example, adding signals that favor regulatory T cell activity reduced the proliferation of harmful gluten-reactive cells and lowered the release of inflammatory messengers such as interferon gamma and interleukin twenty-one. These observations support the idea that restoring the strength or function of regulatory T cells could calm the disease process.

Consistency, Safety, and Open Questions

Results across high-quality studies were broadly consistent: transglutaminase 2 inhibition reduced gluten-induced intestinal injury and inflammation, and regulatory T cell–directed strategies showed the ability to restrain harmful immune responses. Symptom scores and quality of life measures improved most clearly at higher doses of the transglutaminase 2 blocker, aligning with the biological markers of protection.

Important questions remain. Most trials were short, with carefully controlled gluten exposure. Longer studies are needed to confirm sustained benefit, to clarify safety over time, and to understand how these treatments perform in everyday life where exposures vary. For regulatory T cell approaches, researchers need practical, scalable ways to enhance these cells safely in people, and to show durable improvements that matter to daily functioning.

How These Findings Could Fit with a Gluten-Free Diet

The gluten-free diet will remain central to care. However, no diet can fully control every situation. Cross-contact in restaurants, travel, school, or shared kitchens can still lead to symptoms and anxiety. Medicines that blunt the immune reaction or reduce the ability of gluten to trigger that reaction could provide an added safety net. They might lessen the damage from accidental exposure, reduce inflammation more quickly after mistakes, and help some people who continue to have symptoms despite being careful with their diet.

What This Could Mean for People with Celiac Disease

This review points to two promising paths that aim at the root of the immune problem. Transglutaminase 2 blockers directly interfere with the enzyme activity that makes gluten more inflammatory, and they showed protection of intestinal structure, fewer inflammatory cells in the lining, and improvement in symptoms during gluten exposure. Regulatory T cell strategies aim to restore the body’s tolerance mechanisms, and early work shows they can quiet the response to gluten and reduce inflammatory signaling.

If future trials confirm long-term benefit and safety, these approaches could complement the gluten-free diet by reducing the harm of accidental exposures and helping the intestinal lining heal more reliably. For people living with celiac disease, that could translate into fewer flares, clearer guidance after slip-ups, and greater confidence when eating outside the home. In short, these immune-targeted strategies offer real hope that care will move beyond avoidance alone and toward treatments that safeguard the gut even when life is imperfect.

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