Tolerance and hematopoietic stem cell transplantation 50 years after Burnet’s theory

In 1949, the original formulation of Burnet's theory on the mechanisms responsible for the capacity of the immune system to discriminate between foreign antigens (i.e., the "non-self") and the cells of its own body (i.e., the "self") was published. Since then, further refinements and reconsiderations of the basic concepts underlying the achievement of a state of tolerance toward a certain antigen have been reported. Here, we attempt to analyze critically new clinical and experimental strategies aimed at inducing alloantigen-specific unresponsiveness. The data discussed in this review are drawn from articles and abstracts published in journals covered by the Science Citation Index and Medline. Induction of tolerance toward alloantigens still remains one of the most elusive goals of clinical immunology. Until now, nonspecific immunosuppressive drugs have been used to successfully perform both solid organ and hematopoietic stem cell transplantation. However, using this approach, patients given an allograft are exposed to the threat of infections, tumors, and other side effects. Moreover, in solid organ transplant recipients, permanent tolerance toward the graft's alloantigens is never achieved. Recently, considerable progress has been made in expanding our knowledge of transplant tolerance. The traditional model of central tolerance, derived from Burnet's concept, has been complemented by knowledge of mechanisms of peripheral tolerance. New experimental and therapeutic trials based on the blockade of costimulatory molecules, as well as on generation and infusion of either regulatory or nonimmunogenic cells, have been recently proposed for inducing alloantigen-specific tolerance.The achievements obtained in understanding the mechanisms of unresponsiveness toward non-self antigens are fundamental prerequisites for successful allogeneic transplants, and they could open a new exciting era of specific, immunosuppressive therapies.