Transplant tolerance: progress and challenges

Organ transplantation has proven to be an effective therapeutic for a wide 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 been 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 (Treg) 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: preexisting memory T cells and "heterologous immunity" in antigen-experienced humans but not in immunologically naïve 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 the cellular and molecular mechanisms by which memory T cells and innate immunity modulate transplant tolerance and detailed immunologic studies of the rare "spontaneously tolerant" patients may lead to development of combined strategies that target and modulate the immune system at multiple levels.