A theoretical framework for self-tolerance and its relevance to therapy of autoimmune disease

Therapeutic intervention in autoimmune diseases should be based on a knowledge of how the normal immune system maintains unresponsiveness to 'self' and how this state of unresponsiveness may be broken. We have proposed that 'self' from the viewpoint of T cells may represent only a small fraction of the peptides that are available in the body. These would be the peptides that successfully access MHC molecules on a limited number of antigen presenting cells. As the number of self peptides is far greater than that of useful MHC molecules, then the set that are privileged to access MHC on presenting cells will compete or buffer out the others. In other words the peptides which are immunologically visible establish tolerance to themselves whilst ensuring that many others remain cryptic. On this model, organ-specific autoimmunity is not a breakdown of tolerance but rather a failure to keep certain peptides from associating with MHC molecules on cells involved in antigen presentation. This could be at either the inductive side of the response or on the target side if mimicry by foreign antigens has primed the effector arm of the immune response. Monoclonal antibodies (MoAbs) have proved to be useful immuno-suppressive agents. MoAbs to certain T-cell adhesion molecules may also permit tolerance to occur to antigens administered simultaneously with them. The possibility of establishing tolerance to exposed peptides in autoimmunity is discussed. We propose that T cells whatever their stage of maturation can be tolerized as long as they see antigen in the absence of helpful stimuli from other cells. © 1988.