Richard Benjamin

A Theoretical Framework for Self-tolerance and its Relevance to Therapy of Autoimmune Disease

Abstract 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.

Tolerance Induction in the Peripheral Immune System

Publisher Summary This chapter discusses the tolerance induction in the peripheral immune system. T-cell tolerance can be induced in mice to the foreign protein human gamma globulin (HGG) by giving that protein under the umbrella of CD4 mAb therapy. By choosing a rat CD4 mAb that cannot kill T cells in vivo , and by using adult thymectomized mice, it can be shown that any tolerance must be determined through the peripheral T-cell system alone. The chapter presents a study that showed that peripheral tolerance is antigen specific and functionally permanent. It arises and is maintained solely within the CD4 + T cell subpopulation, as CD8-depleted mice are equivalently tolerizable and maintain their state of tolerance indefinitely. The most remarkable feature of the model is that within tolerant animals, the CD4 compartment contains cells capable of resisting normal T cells from breaking that tolerant state, when these cells are transferred from a normal donor to the tolerant host. This suggests that the tolerant CD4 + T cells are not inert or nonfunctional but are capable of interacting to inhibit the function of non-tolerant cells.