When an antigen is administered orally, the immune system does not respond to it; this phenomenon is called “oral tolerance”. This is antigen-driven and has some therapeutic applications in organ-specific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and human rheumatoid arthritis. Two main mechanisms have been proposed to explain antigen-driven tolerance: clonal anergy and active suppression. Central role in the development of oral tolerance plays the gut associated lymphoid tissue in this area TH2 T cells response predominates; these T-lymphocytes produce IL-4 and IL-5 following oral administration of an antigen. Low doses of antigen favor the development of active suppression that is antigen driven regulatory cell induced tolerance. High dose of orally administered antigen results in the presentation of antigenic fragments via MHC-class II molecules in the T-lymphocytic clones; these clones recognize antigen-MHC-II complexes, in the absence of “second signal” and possibly in the absence of other costimulatory signals. Thus, the clones which possess T cell receptors specific for this particular antigen undergo anergy.

Nuclear cytoplasmic ribonucleoproteins (well known autoantigens) are highly conserved across species. Such antigens could be used in oral tolerance studies in patients with autoimmune disease. Instead of using the entire molecules it may be better to use their immunodominant T-cell epitopes. Mapping of T-cell epitopes is a difficult task. Analysis of known cytotoxic and helper T cell epitopes has revealed comparative similarities within their primary sequences. These common motifs allow to predict the sequences of a protein that are likely to be immunodominant T-cell epitopes. Thus, peptides can be synthesized corresponding to amino acid sequences of autoantigens, previously predicted to contain T cell epitopes by an algorithm based on amino acid motif. Again a problem limiting the use of peptides as tolerogens is their instability because these are rapidly degraded by proteases. However, it is possible to replace the standard peptides with pseudopeptides and peptide mimetics. The production of such peptides can be achieved by the introduction of backbone modifications into biologically active peptides, such as changes in the amide bond (CO-NH); therefore the enzymatic stability and the conformational properties result in some cases in the production of analogues with improved biological activity. This is a more sophisticated approach of using peptides corresponding to T-cell epitopes of autoantigens in order to induce oral tolerance in patients with autoimmune diseases.