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Immunological Aspects of Transplantation
More than fifty years have passed since the first identical twin transplant was per-formed, and we can now look on organ transplantation as an extremely successful treatment for hundreds of thousands of patients who would otherwise have been doomed to organ failure or to death. This successful kidney transplant between identical twins in 1954, performed at the Peter Bent Brigham Hospital by Dr. Joseph Murray and his colleagues, helped to usher in the field of solid organ transplantation. Within the ensuing decade, this transplant was followed by the first successful trans-plants from a non-twin living donor and later on from a cadaveric donor. The short-age of donor organs is now the chief stum-bling block to further development.
The first twin transplant confirmed that a young, healthy donor could survive with one kidney with no disability, as long as the single remaining kidney was not dam-aged. Indeed, the donor of the first twin transplant is still alive more than fifty years later. This achievement, which was quickly repeated in a number of other twin trans-plants, confirmed the surgical aspects of this operation. Two other important obser-vations were made. First, if the patient suf-fered from an autoimmune nephritis, this could recur in the transplanted kidney. The same disease could also develop in the donor’s remaining kidney because of the genetic susceptibility of identical twins to similar diseases.
The immunological obstacles, however, proved to be stubborn. Medawar and colleagues had shown that skin grafts were destroyed by a mechanism that had immune characteristics. Having reacted against one skin graft, the recipient of a second skin graft from the same donor would react more violently, demonstrating an acquired immunity and a memory for the first tissue. A few years later, Medawar and colleagues demonstrated a natural way of overcom-ing graft rejection, which occurs in fraternal animal twins. The definitive experiment, injecting cells from an inbred strain of mice into the fetus of another strain, resulted in graft acceptance in survivors of this proce-dure and established the concept of immu-nological plasticity in the embryo before the immune system fully develops. Although this had no obvious clinical application, it raised the question about whether this state of immunological plasticity could be tem-porarily induced in a potential organ graft recipient so that the graft would be accepted even though the immune defenses would be rapidly restored.
The ensuing story of immunosuppres-sion still has this aim of “tolerance” in view. Clinical immunological tolerance occurs when the recipient’s immune system is ablated and replaced by hematopoietic stem cells from a donor matched according to expression of human leucocyte antigens (HLAs).
Refinements in immunosuppres-sion include more precisely dosed irradia-tion as well as drug and antibody treatment to support engraftment. Clinicians tend to add more potent immunosuppressive agents to the patient’s therapy. More recent attempts to achieve graft acceptance with minimal immunosuppression are begin-ning to meet with some success. One exam-ple is the use of the lympholytic monoclo-nal antibody, alemtuzumal (Campath-1H), as an inducing agent, followed by mainte-nance therapy with reduced-dose calcineu-rin inhibitor monotherapy.
The interest in organ transplantation greatly stimulated the science of immunol-ogy. Mechanisms of graft rejection are now well understood, and the fate of a graft depends not only on surgical technique but also on the degree of HLA matching between donor and recipient. The specific transplanted organ also has relevance, such as the liver, which is more tolerogenic than others. The HLA system of antigenic deter-minants arises from genes on human chro-mosome 6. The ABO antigen system is also important in solid organ graft outcome but does not directly affect hematopoietic stem cell transplantation (HSCT).
Of the drugs used to suppress the immune system, each has some side effects specific to the agent in question and oth-ers common to all immunosuppressive agents, namely, increased susceptibility to infections and tumors, especially lym-phoproliferative disorders. A strategy of using different agents together to maximize immunosuppression and minimize side effects has been partially successful, and the new approach of minimal immunosuppres-sion should be of additional benefit. Active agents vary from small molecules (azathio-prine and corticosteroids) to complicated peptides and macrolides (cyclosporine, tacrolimus, and sirolimus) and onto large polyclonal and monoclonal antibodies.
Much interest has recently focused on blocking the secondary and tertiary signals of antigen recognition. In animal models, such blockade can result in long-term graft acceptance without other potentially toxic immunosuppressive agents. These and other immunosuppressive agents are in the process of early clinical trials and no doubt will have an effect on immunosuppression in the future.
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