Update on transplantation tolerance

Abstract

The induction of transplantation tolerance has become a major goal, because modern immunosuppressive therapy has not improved chronic rejection rates, and is associated with significant side effects. This article aims to explain the principles of immunological tolerance. Mechanisms of central tolerance involve deletion of self-reactive T cells. Mechanisms of peripheral tolerance are reviewed and also the identification of a subset of regulatory T cells which are characterised by the expression of the transcription factor FoxP3. Interesting recent insights on the role of the ‘anti-inflammatory’ cytokine transforming growth factor β which can ultimately lead to the generation of inhibitory Tregs or inflammatory Th17 cells (CD4 helper T cells which secrete the pro-inflammatory cytokine IL17) are discussed. There are many ways to induce experimental tolerance in animals, however these are difficult to translate tolerance into the clinical context. In addition, standard immunosuppressive agents are calcineurin inhibitors which block T cell activation and IL-2 production. These drugs not only inhibit the activation of effector T cells, but also Tregs, therefore inhibiting Treg driven tolerance induction. Other classes of immunosuppressive drugs should be introduced into the clinic to allow for the possibility of tolerance induction. Strategies to modulate immune responses following transplantation and their potential risks are discussed.