Advances in transplantation tolerance.

Abstract

Immunosuppressive drugs developed in the past two decades have improved the short-term survival of organ allografts, but tolerance has not been achieved and almost all transplant recipients continue to require drugs throughout life. Graft rejection arises from the cognate interaction of T cells with antigen-presenting cells, the recognition of alloantigen through the T-cell receptor, and the delivery of accessory stimulation signals. Once activated by the specific antigen, replicating T cells die if they are re-exposed to the same antigen. Since depletion of antigen-activated T cells is one critical mechanism of transplantation tolerance, drugs such as ciclosporin that interfere with activation-induced T-cell death could inhibit tolerance, whereas drugs such as mycophenolate mofetil, that induce the death of activated T cells, could facilitate tolerance. Other tolerance mechanisms depend on inactivation rather than elimination of allograft reactive T cells. When antigen recognition occurs without costimulation through the CD28 and CD154 accessory receptors, or in absence of cell division, T cells become unresponsive. Thus, inhibitors of CD28 and CD154, and inhibition of T-cell division by rapamycin promotes transplantation tolerance.