The general pattern of immunosuppression world wide for all organ transplants is to combine agents each in small doses so as to get an added immunosuppressive effect, but without individual side effects of the different drugs. Thus, commonly Azathioprine, Cortico-steroids and Cyclosporin are used together. Each has different main side effects. Cortico-steroids stunt growth and cause a round face and impair the healing of wounds. Azathioprine can inhibit the bone marrow and cause anaemia and a low white cell count. Cyclosporin can cause increase in growth of hair and damage the kidney. When these three agents are used together the patient can generally tolerate the immunosuppression well. Unfortunately acute rejection crises can still occur and are usually treated with a short course of high dose steroids or anti-lymphocyte globulin preparations. This powerful immunosuppression for rejection may lead to infection particularly with viruses, causing severe cold sores and may activate cytomegalic virus infection which can cause a temperature and specific bad effects on a variety of different organs. All immunosuppression predisposes a patient to infection and tumour formation.

Despite these worries, most patients do well with organ grafts and after a time can be maintained with relatively low dosage of immunosuppression. With few exceptions however, stopping immunosuppression usually leads to acute rejection and chronic rejection which is difficultto detect and can occur insidiously after years of good function of a graft. Many of us working in transplantation feel that the burden of continuous immunosuppression could potentially be lifted, but more research is needed. We have a number of new immunosuppressive agents, powerful monoclonal anti-lymphocyte antibodies and new drugs. Sirolimus (FK506 and Celcept mycophenolate mofital) have both recently been registered and it is likelythat Rapamycin will soon also be registered. It is important that the addition of these powerful new immunosuppressants doesn't lead to overkill without any benefit to patients.

In the laboratory there are a number of successful models of tolerance, that is, the induction of a state of non- responsiveness in the recipient towards the graft without the requirements of continued drug dosage. To manipulate the immune system in this way is probably more difficult in man than in most animals in whom the experiments are being carried out. It may be that the next stage will be what I call, 'Almost Tolerance' in which after a period as an induction the patient is required to take only a minimal dose of maintenance immunosuppression to prevent the tolerant state being upset by a new immunological challenge, for example, an infection or a bee sting.

The achievements of tolerance probably requires an active process between donor and recipient, which I have likened to a football match and the immunosuppressive drugs are necessary to keep at bay "hooligans'', that is the active lymphocytes which are of great value in times of war or when the patient is threatened with an infection, but are harmful to a graft. If the engagement of donor recipient can be allowed to occur like a football match then when the game is finished the team shake hands and the graft is accepted. This window of opportunity for immunological engagement or WOFIE may be a requirement before a tolerant state can be produced and it is likely that excessive immunosuppression, in addition to thc well known dangers, might prevent the football match from taking place, that is, could prevent tolerance from occuring.

 

Last modified: 11 May 2000