Organ transplantation has proven to be an effective therapeutic for a large variety of disease states, but the chronic immunosuppression required for allograft survival increases the risk for infection and neoplasia. In the past 50 years, a wealth of experimental data has accumulated relating to strategies to preserve function and prolong graft survival. These strategies operate by inducing peripheral or central tolerance to the allograft, with protocols based on regulatory T cell induction as the most promising ones. However, as these protocols move into the clinic, there is recognition that little is known as to their efficacy when confronted with the human immune system: pre-existing memory T cells and 'heterologous immunity' in Ag-experienced humans but not in immunologically naive rodents, infections and early activation of innate immune response and the related inflammation-induced cytokine milieu that inhibit Treg activity while augmenting the T effector response, all pose significant barriers to tolerance induction.

A better understanding of cellular and molecular mechanisms by which memory T cells and innate immunity modulate transplantation tolerance and detailed immunological studies of the rare 'spontaneous tolerant' patients may lead to development of combined strategies that target and modulate the immune system at multiple levels.

Since the first successful renal transplantation in Boston in 1954, more than a million such procedures have been performed worldwide. By strikingly minimizing the incidence of acute rejection, immunosuppressive drugs have led to overall improvements in allograft and patient survivals. However, the improved short-term survival rates have come at a cost: these drugs generally need to be given for the entire life, induce many indirect and direct side-effects and pose an increased risk of life-threatening complications, infections and malignancies. Furthermore these therapies have had little effect on the inexorable loss of transplanted organs because of chronic allograft rejection.

Recent trends in long-term survival rates have indicated a progressive improvement of renal allograft half-lives, but this has been only observed in patients who never had an acute rejection episode. These data emphasize the critical role of the recipient’s alloimmune response as a major determinant of transplant outcome and highlight the need to develop novel strategies to induce immunologic donor-specific tolerance defined as a lack of a destructive immune response towards the graft in the presence of generalized immune competence. Ideally, tolerance should also translate into a lack of chronic rejection and late graft loss.