Evolution of 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).
Until the discovery of cyclosporin in the late 1 970s, steroids and azathioprine were used for immunoprophylaxis. During the cyclosporin era the monoclonal antibody OKT3, directed against the CD3 molecule expressed on T-lymphocytes, also became available and was sometimes used along with cyclosporin based regimens as immunoprophylaxis (especially in North American centres) or to treat steroid resistant graft rejection. The 1990s can be regarded as the modern era of immunosuppression. Although cyclosporin is still the mainstay of many immunosuppressive regimens, several new agents have now been introduced. The place of cyclosporin has been challenged by tacrolimus and other important immunosuppressive agents have recently become available, including mycophenolate mofetil, rapamycin and monoclonal antibodies directed against the interleukin-2 (IL-2) receptor (CD2S). When considering immunosuppressive therapy for organ transplantation, the transplant surgeon is now faced with an increasing range of different agents from which to choose .
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. Cosmetic side effects may beparticularly distressing for the patient. The calcineurin blockers have a relatively small therapeutic window, and monitoring of whole blood drug levels is an important guide to optimal therapy. If, after renal transplantation, the graft fails to function immediately because of acute tubular necrosis, calcineurin blockers may be withheld temporarily to avoid the risk of drug-induced nephrotoxicity. The relative efficacy of cyclosporin and tacrolimus in preventing graft rejection is broadly comparable, and the choice between the two agents is dependent on the preference of the transplant unit and on individual patient tolerance to the different side effects of the two 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 in the liver to its active metabolite 6-mercaptopurine which blocks purine metabolism and thereby inhibits cellular proliferation. Mycophenolate is a recently introduced antiproliferative agent that, after ingestion, is converted to its active metabolite, mycophenolic acid. It inhibits the enzyme inosine monophosphate dehydrogenase that is the rate limiting enzyme in the de novo pathway of purine nucleotide synthesis. Because lymphocytes do not have a salvage pathway for purine synthesis, their ability to proliferate is selectively impaired.
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.
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 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.
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).
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