TWO TYPES OF RECOGNITION: Direct recognition occurs when the recipient's T cells recognize allogenic antigens presented by the donor antigen presenting cells. Indirect recognition occurs when donor antigens on recipient antigen presenting cells are recognized. DIRECT RECOGNITION: Direct recognition occurs during the first days or weeks after transplantation when naive recipient cells recognize donor dendritic cells that have migrated to secondary lymphoid organs. This explains why acute rejection occurs mainly during the first weeks after transplantation. INDIRECT RECOGNITION: This is certainly a less intense mechanism than direct recognition. It probably is involved in acute rejection but is known to play a major role in chronic rejection. CD4 cells that have been activated by indirect recognition play an essential role in activating B cells, leading to the formation of anti-HLA antibodies as well as in activating macrophages and monocytes, endothelial cells and smooth muscle cells. INDUCTION OF TOLERANCE: Three mechanisms of action for regulating the allo-immune response leading to graft tolerance have been put forward: consumption of interleukin-2, production of suppressive cytokins, direct or indirect suppressive contact. T CELL ACTIVATION: Knowledge of the intracellular signals induced by T cell receptor activation makes it possible to target key proteins that could be blocked leading to better immunosuppression than with calcineurin inhibition.