Peripheral tolerance to alloantigen: strategies for the future

The mature, adult immune system is specifically designed to eliminate any foreign material that may enter the body, but not to respond to the body's own tissues and molecules. Indeed, during development, the potential of the immune system to respond to self antigens is removed, by eliminating or effectively silencing any autoreactive cells. These features are well adapted under normal circumstances, as they result in the efficient elimination of potentially harmful agents thereby protecting the body from infection and malignancy. However, in the context of transplantation, this 'normal' response is diametrically opposed to the desired clinical outcome, which is clearly the long term function and survival of the transplanted tissue. To prevent graft rejection the immune system of the transplant recipient has to be manipulated to ensure that it is incapacitated. Immunosuppressive drugs can be used for this purpose and are undoubtedly effective; indeed they have had a dramatic impact on success rates in clinical organ transplantation. However, as the mechanism of action of these chemical immunosuppressants is immunologically non-specific, any immune response the recipient may need to make after transplantation, as well as the rejection response, is suppressed. In addition, to maintain graft survival the drugs have to be taken indefinitely after transplantation and therefore their use is not only associated with immunological complications such as increased risks of infection and malignancy, but also numerous non-immunological side-effects. One way to overcome these problems would be to develop strategies for specific immunosuppression, such that only leukocytes capable of responding to the foreign histocompatibility or alloantigens expressed by the transplanted tissue would be affected. The ability to manipulate or reprogramme the adult immune system in such a way as to induce specific immunological unresponsiveness or tolerance to the alloantigens of the organ donor would offer many advantages over conventional immunosuppressive therapy. Only leukocytes reactive with donor alloantigens would be affected, thus allowing transplant recipients to respond effectively to other immunological stimuli, such as virus infections.