Organ transplantation started in the mid-1950s with a kidney transplant between identical twins, demonstrating the surgical technique could provide successful therapy. The immunological barrier to be overcome, however, proved to be far more difficult to deal with. The introduction of immunosuppressive agents produced some success but it was not until Cyclosporin became available in the 1980s that results became sufficiently good for widespread acceptance and rapid development of organ grafting. Now with more powerful and selective agents, although there is still much room for improvement in immunosuppression, one of the main problems in organ transplantation is a result of its success, namely a shortage of organ donors. In this review, I summarise these matters.
Keywords: organ transplantation, immunosuppression, donor shortage
Organ transplantation did not exist as clinical therapy until the mid 1950s yet in the intervening years it has developed at a remarkable rate from a procedure considered to be dangerous and irresponsible to a "gift of life" to around a million people, who were otherwise doomed due to untreatable and fatal disease of vital organs. In the last few months, more than 10,000 health care workers have attended two international meetings on organ transplantation, one in Boston and one in Paris and although the pace of scientific advance has slackened there are still many problems to be overcome, the greatest is to find enough organs for patients in need. This is a malady resulting from the success of organ transplantation.
I will consider three aspects of organ transplantation, namely the technique, the immunological barriers, and the ethical dilemmas.
The early work on the science of transplantation was performed with skin grafts. Techniques have been available for centuries for grafting using a flap or free-grafting using very thin slices of the skin. In both techniques, development and maintenance of the blood supply of the graft is essential. In a flap graft, some blood vessels are preserved; in a free graft, new vessels have to grow into the living tissue, which is extremely vulnerable until vascularisation is established, since nourishment depends solely on diffusion of vital materials to the graft and removal of waste products from the graft. Once blood vessels are established the graft is robustly viable but becomes subject to immunological rejection. The classical studies by Medawar and his colleagues in the 1940s, showed that rejection was an active immunological process, involving an "immunological memory" similar to that which develops after an infectious disease, so that a second graft from the same donor to the same recipient was rejected much more quickly than the first (1).
A method of overcoming graft rejection was observed in skin grafts performed between non-identical cattle twins by Medawar's group who found to their surprise that the grafts were not rejected (2). Subsequently an explanation of this phenomenon of "natural immunological tolerance" was attributed to the unusual cross-circulation of blood in the placenta of non-identical cattle twins, which seldom occurs in other species. Thus the plasticity of the immune system during embryological development became a subject for study. Following up on their observations in the cattle twins Medawar's group found that injection of cells experimentally from an inbred strain of mice into a different strain during embryonic development by intra-uterine or neonatal injection resulted in graft acceptance for prolonged periods but not always indefinitely (3).
An important complication of this procedure was observed by Billingham and Brent, namely a wasting disease known as "graft-versus-host" disease in which the injected cells, if they were immunologically competent, could destroy the host (4).
This is an important consideration in any attempts at therapeutic tolerance in which immunologically active cells are used as a vehicle to promote tolerance. …