[Collagen in the treatment of rheumatic diseases--oral tolerance]

The term "oral tolerance" means antigen specific suppression of immune response after oral application of antigen. Primary mechanisms by which oral tolerance is mediated include: deletion, anergy and active cellular suppression. The determining factor in this process is the dose of applied antigen. High doses of antigen develop deletion and anergy of cells while low doses of antigen result in bystander suppression. Recently bystander suppression has attracted attention in the treatment of autoimmune diseases. This process is connected with induction of regulatory T cells of Th2/Th3 phenotypes in gut with characteristic profile of anti-inflammatory cytokines as IL-4, IL-10 and TGF-beta. By means of circulation the lymphocytes enter the affected place and when meeting again with the antigen, they produce the same profile of cytokines which they originally made in the gut. These cytokines then suppress local autoimmune and inflammatory reaction independently of the antigen type. After successful trials of treatment with low doses of orally applied collagen type II in animal models of experimental arthritis, this treatment was also studied in clinical trials in humans with rheumatoid arthritis. Although the results obtained to this date are very promising they can not be considered final. Several questions still need to be solved: identification of responders, determination of character and amount of collagen applied as well as the route of application. Another promising therapeutic approach could be the simultaneous application of collagen and the compounds enhancing the cell response of Th2 or Th3 lymphocytes such as TGF-beta, IL-2, antibodies to IL-12 which can augment the oral tolerance. In clinical praxis the treatment of osteoarthrosis with collagen type I has also been successfully applied. Induction of oral tolerance is new approach in the treatment of rheumatoid arthritis and as each new therapy, it requires refinement. In the future it is expected that an improved study design and a better understanding of the underlying mechanisms of oral tolerance will lead to an increased efficacy of the therapy in humans similar to the effectiveness previously demonstrated in animal models.