New strategies in immune tolerance induction

Induction of tolerance in clinical organ transplantation that will obviate the use of chronic immunosuppression and preserve host immune response to other antigens remains the goal of transplant research. The thymus plays a critical role in the ability of the immune system to discriminate between self- and nonself-antigens or harmful and harmless alloantigens. We now know that multiple factors determine how the immune system responds to a self-antigen or foreign antigen. These determinants include developmental stage of the host, stage of T-cell maturity, site of antigen encounter, type and maturity of antigen-presenting cells, and presence and type of costimulatory molecules. Our understanding of the mechanisms of T-cell interactions with peptide/ major histocompatibility complex in peripheral lymphoid organs has led to experiments that translate into peripheral T-cell tolerance. The induction of high-avidity peripheral alloreactive T cells in the early phase of organ transplantation makes it difficult to achieve long-term alloantigen-specific tolerance without the use of transient perioperative immunosuppression. Therefore, protocols that induce robust tolerance in rodent and nonhuman primate models involve the use of donor antigen combined with a short course of perioperative immunosuppression. These studies suggest that the underlying mechanisms of peripheral tolerance include deletion, anergy, immune deviation, and regulatory T cells. This review focuses on recent advances in tolerance induction in experimental animal models and discusses their relevance to the development of protocols for the induction and maintenance of clinical transplant tolerance.