Mechanisms of Allograft Tolerance

Organ transplantation's considerable benefit is countered by the risks associated with its requirement for chronic immune impairment to prevent rejection. Although improved understanding of the mechanisms of rejection have allowed incrementally more specific immunosuppressive medications, stubbornly poor long-term patient outcomes continue to indicate that immunosuppressive drug toxicity remains problematic. For at least 60 years, it has been known that, under certain circumstances, allograft recipients can be induced to become tolerant of their grafts, maintaining organ function and immune competence without the need for ongoing drug therapy. This chapter will provide an overview of the predominant mechanisms by which tolerance is induced and maintained: chimerism, depletion, co-stimulation blockade, and regulation; and introduce B-cell mechanisms of tolerance. It will highlight those therapeutic maneuvers that are translatable, and provide a framework with which to interpret clinical tolerance trials.