Oral immunomodulation therapy in rheumatoid arthritis.

Because the gastrointestinal mucosa is a vast interface between the body and the environment, it is the main entry site for many environmental antigens. Enterocytes can cleave environmental antigens into peptides, bind these peptides to their CD1 receptor, and present them to T cells. Intact antigens can penetrate through specialized Peyer's patch enterocytes called 'M cells'; they are then degraded and presented by dendritic cells to Peyer's patch T cells. The influx of multiple antigens through the gastrointestinal mucosa usually results in tolerance. High-dose tolerance is due to T cell deletion or anergy, whereas low-dose tolerance involves activation of TGFbeta-producing Th2 or Th3 cells. TGFbeta inhibits lymphocyte proliferation and the production of antibodies to ingested antigens; in addition, it blocks the proliferation of lymphocytes in organs to which gastrointestinal Th3 lymphocytes migrate. This 'innocent bystander' effect has been used to try to induce oral tolerance. For instance, pretreatment with oral bovine type II collagen has proved capable of modulating several models of experimental polyarthritis. Arthritis severity was considerably reduced. Preliminary attempts in humans with rheumatoid arthritis have yielded promising results.