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fic clones. A second strategy is through affecting T-cell subset choice by deviation of the T-cell system from one differentiation arm to another, such as Thl to Th2 or Th3. The change in cytokine pattern produced by the same clone might be able to prevent specific damage, as well as provide protection by bystander suppression. A third strategy is the use of regulatory peptides derived from the T-cell receptors themselves, which are employed by the organism to bring about homeostasis through suppression of unwanted reactivity. Fourth, treatments directed against an important receptor or its mediator can have a curative effect in some cases. Finally, viral vectors carrying genes coding for specific antigen products, and/or ameliorating agents such as cytokines and chemokines have been shown to be potent response modifiers. Each of these classes of agents will now be considered in greater detail.

Immune Tolerance Induction

If immune tolerance is defined as the state in which response to a particular immunogen is absent, this would include cases in which the specific precursor T or B cell is deleted/anergized, or exhausted through chronic expansion of precursors. It would also include immune deviation where the cell in question does not become immunologically silent but rather follows a different functional program. In fact, systemic introduction of a native antigen or peptide, or one that has been modified to increase its affinity for the MHC or TcR, can induce deletion of clones with the highest affinity for the antigen. A feature of self-antigens is that under usual conditions, the B and especially the T cells directed against the most dominant self determinants will have been removed owing to deletional mechanisms in the thymus and periphery, leaving a rather large assemblage of lymphocytes directed against subdominant and cryptic determinants. This protected repertoire can be engaged under highly inflammatory conditions. The secondary determinants, which appear to then be the dominant ones, and which can activate this protected repertoire, can be removed by appropriate antigenic administration, and this may suffice to prevent autoimmunity. Another mechanism of T-cell deletion is brought about by apoptosis of specific lymphocytes, via antigen-induced T-cell death. Apoptosis can represent the final mechanism of both exhaustion and deletion.

One important feature of autoimmune pathology is that the initial response, which may be directed against a single or small number of antigenic determinants, then diversifies to include many more determinants and a broader repertoire of T cells, in what has been termed intramolecular and intermolecular determinant spreading. Thus, it appears to be important to regulate T cells directed against the initiating determinant. It has also been shown that tolerance induction to the secondary determinants plays a role in the prevention of spreading. It becomes necessary to consider how the response that has been established can be diverted effectively, and this will be the most difficult aspect of therapeutic



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