Mucosal tolerance: a two-edged sword to prevent and treat autoimmune diseases

Mucosal administration of autoantigens results in the development of a state of peripheral immunological tolerance. Depending upon the dose of antigen administered, anergy/deletion of antigen-specific T cells (higher doses) and/or selective expansion of cells producing immunosuppressive cytokines (TGF-beta, IL-4, and IL-10) (lower doses) are two major mechanisms in mucosal tolerance induction. Mucosal tolerance is more effective after nasal compared to oral administration of antigens at the same dose. A large series of studies have demonstrated that mucosal tolerance by oral or nasal antigen administration effectively prevents several experimental disease models (EAE, EAMG, EAN, EAU, IDDM, and CIA). Mucosal antigen administration is superior in prevention to treatment of autoimmune diseases. To broaden the effectiveness of mucosal tolerance, a conjunction of tolerogens with cytokines/CTB might enhance suppression of clinical disease. Based on experimental experience with mucosal tolerance, trials in humans are ongoing in MS, RA, and uveitis. However, mucosal tolerance induction is related to the route of antigen administration (oral, nasal, parentetal), type of antigen (whole protein, peptide, altered peptide), and timing with regard to disease onset and may represent a two-edged sword. In particular, the risks of worsening an ongoing autoimmune disease by mucosal antigen administration have been incompletely addressed. Here we give an overview on some recent developments in this field where, however, much more studies are needed to define an ultimate and safe procedure.