T cell targets for tolerance induction to alloantigens: Strategies and mechanisms

The study of transplantation tolerance has been a major area of immunological research since the pioneering work by Medawar and colleagues. It has been classically defined as the absence of an immune response to a specific antigen in the setting of a normal immune response to all other antigens. The induction of tolerance to alloantigen in the transplantation setting would not only allow better graft survival but would also obviate the need for immunosuppressive therapy. Induction of tolerance is considered by many clinicians to be the 'holy grail' of organ transplantation but despite many years of experimental research on tolerance induction, reliable induction of allograft tolerance has not been achieved in humans. The four fundamental mechanisms of T cell tolerance that may be operating in the transplantation setting are deletion, anergy, ignorance and regulation/suppression. Several strategies to induce tolerance in transplantation have been employed; however most of these tolerogenic strategies have been investigated in rodents and it remains to determine whether they can be transferred into large outbred animal models or clinical transplantation.