Shixin Qin

Reprogramming the Immune System for Peripheral Tolerance with CD4 and CD8 Monoclonal Antibodies

The basic aim of therapeutic immunology is to manipulate the immune system in order to avoid or reverse a variety of diseases with an immunologic component. Where the disease is caused by an infectious agent it has often been possible to use vaccination or passive immunization to protect the individual against both the infection and any pathogenic consequences. However, when it is the case that the immune system has already made an inappropriate response, either to an external agent such as a parasite or allergen, or to a normal tissue such as the pancreas (diabetes) or brain (multiple sclerosis), it has so far proved far more difTicult to intervene. Generalized immunosuppression can act to damp down the disease processes, but at the cost of suppressing immunity as a whole and risking opportunistic infection. What is needed is a way to suppress or reinduce tolerance in the T cells which are driving the disease, while leaving the rest of the immune system relatively intact. Monoclonal antibodies against functional molecules on the T-cell surface are now providing us with the tools to manipulate the immune system in just this way. The mature immune system of the adult is programmed to destroy foreign material entering the body but not to react with self tissues. Central to this self tolerance is the deletion or inactivalion of autoreactive T-cell ciones during ontogeny. It has long been recognized that the thymus plays a crucial role in this process as it is the primary site for T-cell differentiation and generation of the antigen receptor repertoire (Pullen et al. 1989). The T cells that emerge from the thymus are strongly biased in their potential reactivity such that processed antigens tend to be seen only when presented as peptides bound to major histocompat-

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 Using CD4 and CD8 Monoclonal Antibodies

The immune system maintains a constant capability to respond to the outside world while remaining unresponsive to self. There may be two broad explanations for self-tolerance. First there must be some self-molecules which are simply invisible or cryptic to the immune system (see Waldmann et al. 1989a). In this case ignorance maintains unresponsiveness. Second, some self-molecules become visible to lymphocytes with complementary receptors and are able to inactivate or “tolerise” those cells. For T-cells the visible antigens would be processed peptides presented on cell surfaces together with the individual’s own MHC Class I and Class II gene products. It is not known for any individual cell or even tissue what number of different peptides are used to define “self”. Some peptides are likely to be ubiquitous (present in all cells), while others may be restricted to defined cell types. Endogenous peptides may be invisible (cryptic) for reasons of quantity, capacity to bind to MHC, and failure to compete in processing, transport and access to MHC molecules.

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.