Immunological Aspects of
Transplantation
INTRODUCTION
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
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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