Immunosuppressive
therapy
In tracing the development of clinical immunosuppression, three
different eras can be identified:
• the early or precyclosporin era (from the early 1960s to the late
1970s);
• the cyclosporin era (from the early 1980s);
• the modern era (the 1990s).
Calcineurin
blockers
Cyclosporin and tacrolimus, although structurally distinct, exert their
principal immunosuppressive effect through the same pathway. Each of the two
agents binds within the T-cell to a particular cytoplasmic protein or
immunophilin (cyclosporin binds to cyclophilin and tacrolimus to FK binding
protein). The resulting immunophilin—drug complex then blocks the activity of
calcineurin (a phosphatase) within the cytoplasm of the T-cell. Calcineurin
plays a critical role in facilitating the transcription of IL-2, the main T-cell
growth factor, and other cytokines after T-cell activation. By blocking cytokine
synthesis, cyclosporin and tacrolimus exert a potent immunosuppressive effect.
The two agents share a number of side effects, the most notable of which is
nephrotoxicity (Table 11.2). Cosmetic side effects may be
Antiproliferative
agents
Lymphocytes are among the most rapidly proliferating cells in the body,
and lymphocyte proliferation and clonal expansion is an integral part of the
immune response to an allograft. The antiproliferative agents available for
immunoprophylaxis are azathioprine and mycophenolate. Azathioprine is converted
Steroids
Steroids have always been an important component of immunoprophylactic
regimens. Glucocorticoids are potent anti-inflammatory agents and have
wide-ranging effects on the immune response. Because of their numerous and
well-known side effects, many centres attempt to withdraw gradually steroids
from patients who have stable graft function at around 1 year after
transplantation, but this sometimes precipitates a rejection episode and
necessitates continued treatment with steroids.
Antibody
therapies
Many North American transplant units also include antilymphocyte
antibody preparations as part of their immunoprophylaxis — so-called
‘quadruple therapy’. A polyclonal antilymphocyte preparation (ALG or ALS)
may be used or, alternatively, a monoclonal antibody directed against CD3 or
CD25 (IL-2 receptor) onTcells may be given. In Europe, the use of antibody
preparations is more common after heart transplantation, where irreversible
rejection is usually synonymous with death of the patient. Antibody therapy is
often used in renal transplantation for patients who are thought to be at
particular risk from graft rejection, for example highly sensitised and second- or third-time graft recipients.
Rapamycin
Rapamycin is a newly discovered immunosuppressive agent that was
isolated from a fungus found on Easter Island. Like tacrolimus, it is a
macrolide which binds within the I-cell to FK binding protein. However, the mode
of action of rapamycin is completely different to that of both cyclosporin and
tacrolimus. It acts by interfering with intracellular signalling from the IL-2
receptor and arrests I-cell division in the G1 phase. Rapamycin and cyclosporin
therefore act at different stages in I-cell activation and their
immunosuppressive effects are synergistic.
Immunosuppressive
regimens
When selecting an immunosuppressive regimen some of the important points
to bear in mind are as follows.
• The challenge is to provide levels of immunosuppression that are
sufficient to protect the graft from rejection without exposing the recipient
to excessive risk from infection and malignancy as a result of nonspecific immunosuppression.
• Immunoprophylaxis is started at the
time of transplantation and continued indefinitely (as maintenance therapy),
although the requirement for immunosuppression is highest in the first few weeks
after transplantation when the risk of acute rejection is greatest.
• Individual immunosuppressive protocols vary somewhat but almost all
use a combination of immunosuppressive agents. All include a calcineurin blocker
(cyclosporin or tacrolimus) as the main agent and this is most often given along
with an antiproliferative agent (azathioprine or mycophenolate mofetil) and
steroids — so-called ‘triple therapy’. Less often, a calcineurin blocker
is used with an antiproliferative agent alone or with steroids alone (dual
therapy).
• A few renal transplant units use monotherapy with a calcineurin
blocker and then add other agents only if needed to treat rejection. At the
other end of the spectrum, some units, particularly those in North America,
advocate the use of antibody induction therapy (monoclonal or polyclonal
preparations) followed by a calcineurin blocker, an anti-proliferative agent and
steroids (quadruple therapy).
• Many renal transplant units reserve the more intensive antibody
induction protocols for recipients judged to be at increased risk of graft
rejection (e.g. highly sensitised recipients and grafts with a poor HLA match).
• The principles of immunoprophylaxis are similar for all types of
organ transplantation. However, after thoracic organ transplantation there is a
tendency to use more intensive immunosuppression than for kidney
transplantation,
in part because loss of a heart or lung graft from rejection almost inevitably
culminates in death. Interestingly, liver grafts seem less susceptible to
graft rejection, for reasons that are still unclear.
• The place of the newer immunosuppressive agents, such as rapamycin
and anti-CD2S monoclonal antibodies, still remains to be established but recent
trials have shown promising results.
Acute
rejection during the first 6 months of transplantation occurs in around 20—40
per cent of transplant recipients. Fortunately, the majority of acute rejection
episodes responds to a short course of high-dose steroid therapy. This can be
given as three daily intravenous doses of methylprednisolone (0.5—1 g/dose) or
a several-day course of oral prednisolone (e.g. 200 mg tapering to 20 mg). If
the response to treatment is inadequate or if acute rejection recurs it can
often be treated successfully by recourse to antilymphocyte antibody therapy
and/or switching from cyclosporin to tacrolimus (or vice versa).