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

Objective. In 1949, the original formulation of Burnet's theory on the mech anisms responsible for the capacity of the immune system to discriminate be tween foreign antigens (i.e., the "nonself") and the cells of its own body (i.e., the "self") was published. Since then, further refinements and recon siderations 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 induci ng alloantigen-specific unresponsiveness. Data Sources. The data discussed in this review are drawn from articles and abstracts published in journals covered by the Science Citation Index and Medline. State of the Art. Induction of tolerance toward alloantigens still remains one of the most elusive goals of clinical immunology. Until now, nonspecifi c immunosuppressive drugs have been used to successfully perform both solid organ and hematopoietic stem cell transplantation. However, using this app roach, patients given an allograft are exposed to the threat of infections, tumors, and other side effects. Moreover, in solid organ transplant recipi ents, 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, derive d from Burnet's concept, has been complemented by knowledge of mechanisms o f peripheral tolerance. New experimental and therapeutic trials based on th e blockade of costimulatory molecules, as well as on generation and infusio n of either regulatory or nonimmunogenic cells, have been recently proposed for inducing alloantigen-specific tolerance. Conclusions. The achievements obtained in understanding the mechanisms of u nresponsiveness toward non-self antigens are fundamental prerequisites for successful allogeneic transplants, and they could open a new exciting era o f specific, immunosuppressive therapies. (C) 2000 International Society for Experimental Hematology, Published by Elsevier Science Inc.