Harnessing Kupffer Cell Metabolic Rewiring: A Novel Approach to Immune Tolerance in Celiac Disease (+Video)

Celiac.com 06/09/2025 - Celiac disease is an autoimmune disorder where the ingestion of gluten—a protein found in wheat, barley, and rye—triggers an immune response that damages the small intestine. The only current treatment is a strict, lifelong gluten-free diet, which can be challenging and socially limiting. Recent research has explored innovative strategies to induce immune tolerance to gluten, aiming to alleviate the burden of dietary restrictions for individuals with celiac disease.

The Innovative Strategy: Rapamycin–Gliadin Nanoparticles

Researchers have developed a novel therapeutic approach using composite nanoparticles that combine rapamycin, an immunosuppressive agent, with gliadin, a component of gluten. These rapamycin–gliadin nanoparticles are designed to be taken up by specific immune cells in the liver and spleen, particularly Kupffer cells (a type of liver macrophage) and splenic dendritic cells. The goal is to reprogram these cells to adopt a tolerogenic, or tolerance-promoting, phenotype, thereby reducing the immune system's adverse reaction to gluten.

Mechanism of Action: Metabolic Reprogramming and Immune Modulation

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Upon administration in a mouse model of celiac disease, the rapamycin–gliadin nanoparticles were efficiently internalized by antigen-presenting cells. This uptake led to a significant shift in the metabolic pathways of these cells—from glycolysis (a form of sugar metabolism) to oxidative phosphorylation (a more efficient energy production process). This metabolic reprogramming was associated with increased levels of itaconate, a metabolite known to have anti-inflammatory properties.

The elevated itaconate levels contributed to the expansion of PD-L1-positive tolerogenic dendritic cells in the spleen and a reduction in pathogenic Th1 cells, which are typically involved in the inflammatory response to gluten. This shift in the immune cell population indicates a move toward immune tolerance.

Experimental Evidence: The Role of Itaconate

Further experiments demonstrated the crucial role of itaconate in this process. Bone marrow-derived macrophages from mice lacking the enzyme necessary for itaconate production failed to induce the tolerogenic dendritic cell phenotype upon treatment with the nanoparticles. However, when supplemented with a derivative of itaconate, these macrophages regained their ability to promote immune tolerance. This finding underscores the importance of itaconate in stabilizing the tolerogenic state of dendritic cells.

Clinical Implications: Toward a Tolerogenic Therapy for Celiac Disease

The study's findings suggest that rapamycin–gliadin nanoparticles can effectively reprogram immune cells to promote tolerance to gluten, thereby reducing intestinal inflammation and damage in celiac disease. This approach represents a significant advancement in the pursuit of antigen-specific immunotherapy for autoimmune diseases. By targeting the immune response at a cellular and metabolic level, this strategy holds promise for developing treatments that could allow individuals with celiac disease to tolerate gluten without adverse effects.

Conclusion: A Promising Path Forward

This research offers a compelling proof of concept for using metabolic reprogramming of liver and spleen immune cells to induce antigen-specific tolerance in celiac disease. By harnessing the body's own immune system and altering its response to gluten, this approach could pave the way for more effective and less restrictive treatments for celiac disease and potentially other autoimmune disorders.

Read more at: pubs.acs.org

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