Alternative approaches for the induction of transplantation tolerance

The immunosuppressive drugs currently in use in clinical transplantation are undoubtedly very effective at controlling graft rejection. However, their use is associated with a large number of side-effects, both immunological and non-immunological, particularly in the longer term. From an immunological point of view, the major disadvantage of these agents is that their mode of action is immunologically non-specific, resulting in blanket or pan-immunosuppression of the recipient's immune system. Thus, not only is the recipient's immune response against the organ graft suppressed, but responses to all other antigenic stimuli such as viral infections are also prevented. The transplant recipient can therefore become severely immunocompromised as a result of the drug therapy and is susceptible to opportunistic infections and an increased incidence of cancer. One of the aims for the design of new immunosuppressive therapy is to develop protocols that are both effective and immunologically specific, such that only the immune response to the transplanted organ is suppressed. The optimal approach would be to induce tolerance to the donor histocompatibility antigens before transplantation, permanently paralysing the ability of the recipient's immune system to mount a rejection response against the graft. Some of the approaches for the induction of immunological tolerance currently being explored in clinical transplantation will be discussed. These include total lymphoid irradiation (TLI) and donor bone marrow transfusion combined with anti-lymphocyte globulin (ALG) post-transplantation. In addition some new approaches for the induction of tolerance before transplantation currently being investigated in experimental systems will be presented.