Tolerance induction in clinical transplantation: the pending questions

Despite the dramatic improvement of early graft survival due to the introduction of cyclosporin, late graft loss caused by chronic rejection and the lethal consequences of long-term immunosuppression, such as infection and cancer, remain major concerns for the transplantation community. Tolerance induction would avoid these complications. The ways to go are controversial, reflecting the redundancy of rejection pathways. They include the induction of central tolerance by establishment of mixed chimerism through hematopoietic stem cell transplantation and the induction of "operational tolerance" through immunodeviation involving dendritic or regulatory T cells. Major advances have been made in animal models exploring these strategies and, some preliminary data are even now available in humans, allowing the initiation of pilot clinical trials. In this article, we discuss the key questions that these trials will have to address.