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 th e body's own tissues and molecules. Indeed, during development, the po tential of the immune system to respond to self antigens is removed, b y eliminating or effectively silencing any autoreactive cells. These f eatures are well adapted under normal circumstances, as they result in the efficient elimination of potentially harmful agents thereby prote cting 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 t he immune system of the transplant recipient has to be manipulated to ensure that it is incapacitated. Immunosuppressive drugs can be used f or this purpose and are undoubtedly effective; indeed they have had a dramatic impact on success rates in clinical organ transplantation. Ho wever, as the mechanism of action of these chemical immunosuppressants is immunologically non-specific, any immune response the recipient ma y need to make after transplantation, as well as the rejection respons e, is suppressed. In addition, to maintain graft survival the drugs ha ve to be taken indefinitely after transplantation and therefore their use is not only associated with immunological complications such as in creased risks of infection and malignancy, but also numerous non-immun ological side-effects. One way to overcome these problems would be to develop strategies for specific immunosuppression, such that only leuk ocytes capable of responding to the foreign histocompatibility or allo antigens expressed by the transplanted tissue would be affected. The a bility 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 ove r conventional immunosuppressive therapy. Only leukocytes reactive wit h donor alloantigens would be affected, thus allowing transplant recip ients to respond effectively to other immunological stimuli, such as v irus infections.