Antigen-specific tolerance approach for rheumatoid arthritis: Past, present and future

Rheumatoid arthritis is a chronic systemic autoimmune disease, affecting mainly the joints. It is caused by an adaptive immune reaction against self-antigens, leading to the over production of inflammatory cytokines and autoantibodies, mainly mediated by autoreactive CD4+ T cells and pathological B cell clones. The treatment options currently available rely on palliative global immunosuppression and do not restore tolerance to self-components. Here, we review antigen-specific tolerance approaches that have been developed to inhibit or delete autoreactive clones, while maintaining a potent immune system for rheumatoid arthritis. The first attempts relied on the oral ingestion of self-reactive peptides, with lukewarm results in human clinical trials. To enhance treatment efficacy, self-peptides have been engineered and combined with immunosuppressive molecules. In addition, several routes of delivery have been tested, in particular, nanoparticles carrying self-antigens and immunomodulatory molecules. More recently, transfer of immune cells, such as tolerogenic dendritic cells or regulatory T cells, has been considered to restore tolerance. Although promising results have been obtained in mouse models, the translation to humans remains highly challenging, mainly because the disease is already well developed when treatments start and because patient's specific self-antigens are often unknown. Nevertheless, these approaches hold great promises for long-term RA treatment.