Rana, JyotiMuñoz, Maite MeleroBiswas , Moanaro2024-05-022024-05-022022-12Rana, J., Muñoz, M. M., & Biswas, M. (2022). Oral tolerance to prevent anti-drug antibody formation in protein replacement therapies. Cellular Immunology, 382, 104641. https://doi.org/10.1016/j.cellimm.2022.104641https://hdl.handle.net/1805/40456Protein based therapeutics have successfully improved the quality of life for patients of monogenic disorders like hemophilia, Pompe and Fabry disease. However, a significant proportion of patients develop immune responses towards intravenously infused therapeutic protein, which can complicate or neutralize treatment and compromise patient safety. Strategies aimed at circumventing immune responses following therapeutic protein infusion can greatly improve therapeutic efficacy. In recent years, antigen-based oral tolerance induction has shown promising results in the prevention and treatment of autoimmune diseases, food allergies and can prevent anti-drug antibody formation to protein replacement therapies. Oral tolerance exploits regulatory mechanisms that are initiated in the gut associated lymphoid tissue (GALT) to promote active suppression of orally ingested antigen. In this review, we outline general perceptions and current knowledge about the mechanisms of oral tolerance, including tissue specific sites of tolerance induction and the cells involved, with emphasis on antigen presenting cells and regulatory T cells. We define several factors, such as cytokines and metabolites that impact the stability and expansion potential of these immune modulatory cells. We highlight preclinical studies that have been performed to induce oral tolerance to therapeutic proteins or enzymes for single gene disorders, such as hemophilia or Pompe disease. These studies mainly utilize a transgenic plant-based system for oral delivery of antigen in conjugation with fusion protein technology that favors the prevention of antigen degradation in the stomach while enhancing uptake in the small intestine by antigen presenting cells and regulatory T cell induction, thereby promoting antigen specific systemic tolerance.en-USPublisher PolicyFVIIIFIXenzyme replacement therapyanti-drug antibodyoral tolerancehemophiliaPompe diseaseTregsLAPIL-10Article