New concepts in tolerance.

Increasing the immunologic specificity of immunosuppressive therapies used to prevent graft rejection is one of the fundamental aims of research designed to develop new approaches for immunosuppression. The objective of work in this area is to identify both strategies and the mechanisms responsible for the induction of tolerance to alloantigens in vivo. Three topics in this area of transplantation immunobiology are considered: (i) The tools available for investigating the induction of tolerance to alloantigens, including T-cell clones, transgenic mice, and neonatal and adult models of tolerance induction. (ii) Strategies for tolerance induction that are being explored in experimental models and in clinical transplantation. These strategies can be divided into two categories: those that aim to induce tolerance in the long term after transplantation and those that aim to induce unresponsiveness at the time of grafting. (iii) The mechanisms responsible for the induction of tolerance to alloantigens. Five nonmutually exclusive hypotheses have been proposed to explain the induction of peripheral tolerance. These are, in broad terms, deletion, anergy, ignorance or helplessness, exhaustion and suppression. The immune status of the recipient may influence which of these mechanisms operates in any particular situation. What is apparent from all studies is that tolerance induction is a dynamic process, and any or all of these mechanisms may be operating at different stages of the induction and maintenance process.