Regulation and privilege in transplantation

Purpose of review Our understanding of transplantation tolerance has undergone numerous paradigm shifts in recent years. These shifts have spawned novel strategies for long-term graft acceptance through reprogramming of the immune system. New paradigms provide the focus of this review. Recent findings Grafts are not merely passive victims, but rather participants. Therapeutic tolerance is an operational term in which the graft is spared damage despite lack of ongoing drug immunosuppression. Graft rejection reflects a cascade of events ranging from inductive events in lymphoid tissue through cell migration, tissue entry and then damage. Tolerance processes can operate at any of numerous checkpoints throughout the cascade. Successful intervention may result from harnessing any of these. Many strategies of therapeutic tolerance are on the basis of the creation of transient ceasefires between graft and immune system. Such ceasefires favour induction of tolerance through the recruitment and induction of regulatory T cells. Regulatory T cells can be found in tolerated grafts and contribute to the acquisition of a state of privilege in those tissues. Summary The potency of regulatory T cells is impressive, but unexplained. Their capacity for expansion in vitro has generated enthusiasm for their therapeutic utility. Future immunosuppressive drugs should preserve regulatory mechanisms and acquired privilege whilst selectively targeting effector functions.