The ability to transplant human organs successfully has developed in the span of a single generation of physicians and surgeons. This remarkable achievement is an excellent example of how animal models may be used to understand and develop treatments for human disease. Organ transplantation is now the preferred treatment modality for a variety of different types of organ failure. Transplantation offers not only improved long-term survival but also improved quality of life for many patients afflicted by renal, hepatic, cardiac, and pulmonary failure.
Enormous effort is currently being expended to develop methods of artificially replacing vital organ functions. Despite these efforts, the ability to replace organ function with mechanical or biomechanical devices remains elusive. While hemodialysis can replace renal function effectively, it offers neither a normal quality of life nor a normal life span. Despite major advances in artificial heart technology, current systems have not reached the point where they can be used routinely to restore normal cardiac function. To date, there are no effective replacements for hepatic or pulmonary function that are suitable for long-term use. Organ transplantation is frequently the only treatment modality that offers a normal lifestyle for patients with advanced organ failure. Recently, successful composite tissue allografts of limbs, face, and larynx have been reported. While these grafts are not lifesaving, it can be argued that for selected patients they reduce misery. This chapter discusses the indications for organ transplantation as well as the limitations to the current state of the art.
With the exception of organs from a genetically identical twin (isografts), all organs from genetically dissimilar individuals (allografts) will naturally be subjected to immunologic rejection. This fundamental biologic limitation has largely been overcome by the development of targeted immunosuppression therapies. These therapies are able to suppress the immunological reactivity that produces graft rejection while leaving intact sufficient immune competency to allow recovery from most infectious diseases. The same degree of success has not been reached when transplanting organs between species (xenografts).
Once it was realized that allografts failed due to an active immunologic attack of the recipient’s immune system on the donor organ, methods of suppressing the immune system were investigated. Early attempts at immunosuppression with substances such as nitrogen mustard and total lymphoid irradiation were unsuccessful because of the toxicity of the therapy. The first practical immunosuppressant was azathioprine, an antimetabolite inhibitor of DNA synthesis. When used in combination with corticosteroids, the first successful combination of immunosuppressants was born and the first boom in the number of transplants occurred. This combination remained the state of the art until it was realized that the cell type that exerts primary control over allograft rejection is the T lymphocyte. This led to the later development of agents able to specifically inhibit activation and proliferation of T cells. The result was immunosuppressants that were both more effective and much less toxic than ...