Challenges to achieving clinical transplantation tolerance

Transplantation is now firmly established as the therapy of choice for end-stage organ failure. Specific immunological tolerance of transplant recipients toward their foreign organ or tissue grafts is a goal that has been sought by transplant biologists for almost fifty years following the original description of the phenomenon in experimental animals (1). Since that time, a wealth of experimental data has accumulated relating to strategies for extending allograft survival and function. Still, the question remains of how near we are to the day when long-term tolerance of engrafted organs or tissues is a clinical reality. With the pharmacopoeia of the transplant biologist continually expanding (2), the potential treatment combinations have become baffling and their impact on strategies to induce tolerance ever more complex. The increasing demand for organ transplantation and the imbalance with the supply of donor organs (3) makes it an urgent necessity to optimize the outcome of clinical transplantation. It is therefore timely to reassess where we stand on the road to achieving clinical transplant tolerance, and highlight the challenges that face us, so that we may choose the best direction in which to invest our efforts in basic and clinical research (4).