For most patients who receive a donated organ, immunosuppressant drug therapy and monitoring of the concentration of immunosuppressants play a critical role in the success of the transplant. Laboratory methods for measuring immunosuppressant drug concentrations in blood include immunoassay, high-performance liquid chromatography (HPLC), and liquid chromatography with mass spectrometry (LC-MS). Clinical laboratories are increasingly using LC-MS for routine measurement of immunosuppressants.
Immunosuppression is used for the following:
• Induction (intense immunosuppression in the initial days after transplantation)
• Maintenance of transplant
• Reversal of established rejection
Forms of immunosuppression include chemical (Box 1), biologic, and irradiation of the lymphoid system or the donated organ. The immunosuppressive activities of therapeutic agents used in transplantation directly interfere with the allograft rejection response. The problem arising from all immunosuppressive techniques is that the person is more susceptible to infection. If infection occurs, immunosuppression must be sus pended, at which time allogeneic reactions frequently develop.
Box1. Immunosuppression in Human Organ Transplantation
Immunosuppressive measures may be antigen-specific or antigen-nonspecific (Table 1). Antigen-nonspecific immunosuppression includes drugs and other methods of specifically altering T cell function. Many cytotoxic drugs are primarily active against dividing cells and therefore have some functional specificity for any cells activated to divide by donor antigens. The use of these drugs is limited by the toxic effects that they may have on other dividing cells or on the physiologic functioning of organs such as the liver.
Table1. Types of Immunosuppressive Treatment
Antigen-specific immunosuppression is an ideal form of immunosuppression. Antigen-specific tolerance is that induced by the infusion of donor cells. This is generally impractical in transplantation, but may be useful in the phenomenon of immunologic enhancement. Enhancement of tolerance has been attempted in renal allograft patients. In a donor-specific blood transfusion program, the patient is transfused several times before elective transplantation with blood from the prospective kidney donor. The overall effect of these transfusions appears to be a tolerance of the recipient to donor transplantation antigens other than those in the HLA-linked regions, such as minor histocompatibility loci, RBC loci, and leukocyte surface antigens. This treatment has greatly prolonged graft survival in these patients.
Cytotoxic Drugs
Cytotoxic drugs are the most common form of therapy and usually include alkylating agents, purine and pyrimidine analogues (Fig. 1), folic acid analogues, or the alkaloids. The drugs of choice, excluding alkylating drugs, are azathioprine, 6-mercaptopurine, 6-thioguanine, 5-fluorouracil, cytosine arabinoside, methotrexate and aminopterin, and vinblastine and vincristine.
Fig1. Pyrimidine analogues (upper row) and purine analogues (lower row) with B and T cell–suppressing activity. A large number of similar compounds are available for human use. (Adapted from Barrett JT: Textbook of immunology, ed 5, St Louis, 1988, Mosby.)
Most immunosuppressive drugs administered alone cannot produce antigen-specific tolerance because they act equally on all susceptible clones. Except for certain drugs (e.g., cyclosporin A), most immunosuppressive agents can be rendered anti gen-specific only by including an antigen-specific element in the tolerizing regimen. In these cases, the drugs act as cofactors in tolerogenesis. Experimental evidence has suggested that these regimens may act as follows:
• Lowering the threshold for tolerance induction
• Blocking the differentiation sequence in cells triggered by antigen
Azathioprine
Since its introduction in 1961, azathioprine, an oral purine analogue that is an antimetabolite with multiple activities, has been the mainstay of antirejection therapy. Azathioprine requires activation to 6-mercaptopurine, which is further metabolized to active 6-thioguanine nucleotides. Metabolites of azathioprine, such as the in vivo metabolite 6-mercaptopurine, are incorporated into cellular DNA. This inhibits purine nucleotide synthesis and metabolism and alters the synthesis and function of ribonucleic acid (RNA). Therefore, azathioprine acts at an early stage in T cell or B cell activation during the proliferative cycle of effector lymphocyte clones. Azathioprine is useful in preventing acute rejection because it inhibits the primary immune response; however, it has little or no effect on secondary responses. Adverse effects include bone marrow suppression, myopathy, alopecia, pancreatitis, and hepatitis. A drug interaction can occur with allopurinol.
Corticosteroids
Corticosteroids can be used in conjunction with azathioprine or other immunosuppressants such as cyclosporine. Corticosteroids directly inhibit antigen-driven T cell proliferation, but steroids do not act directly on the IL-2–producing T cell. They do, however, inhibit production of lymphokines by preventing monocytes from releasing IL-1, thereby blocking IL-1–dependent release of IL-2 from antigen-activated T cells. Other activities of monocytes, such as inhibition of chemotaxis, are also likely to be important in the immunosuppressive process.
High doses of corticosteroids are used to treat acute rejection. In addition, steroids probably reverse in vivo rejection episodes by preventing the production of IL-2, which would inhibit activated T cells as an essential trophic factor.
Cyclosporine (Cyclosporin A)
Cyclosporine, isolated in 1971 from the fungus Tolypocladium inflatum, has become the mainstay of immunosuppressive therapy in transplantation. Cyclosporine affects T cells preferentially by inhibiting the induction of cytotoxic T cells. Unlike corticosteroids, cyclosporine does not inhibit the capacity of all accessory cells to release IL-1. Cyclosporine blocks calcineurin to the IL-2 gene transcription pathway and the release of certain other lymphokines (e.g., IFN-γ). Cyclosporine binds to cyclophilin and the complex binds to and inhibits calcineurin (a protein phosphatase). This prevents activation of the IL-2 transcription factor.
The secretion of B cell growth and differentiation factors by activated T cells is also inhibited by cyclosporin A. Therefore, under the influence of cyclosporin A, Th cell–dependent B cells are not fully activated because of a lack of necessary Th cell stimulation. In pharmacologic doses, however, cyclosporin A does not grossly interfere with the activation and proliferation of sup pressor T cells. Studies have shown prolonged renal allograft survival with cyclosporin A, despite potential mismatches of the HLA system. Adverse effects of corticosteroids include fluid retention, electrolyte abnormalities, hyperglycemia, hypertension, peptic ulcer disease, osteoporosis, and adrenal insufficiency. Hepatotoxicity has been observed in 4% to 7% of patients. Drug interactions can occur with grapefruit juice, erythromycin, oral contraceptives, and a variety of other drugs. Drug monitoring is critical because of the narrow therapeutic range.
A newer cyclosporine microemulsion offers the advantage of improved trough measurement correlation with the actual patient circulating concentration.
Tacrolimus
Tacrolimus (FK-506), a macrolide with mechanisms similar to that of cyclosporine, is derived from a fungus, Streptomyces tsukubaensis, found in soil samples in Japan. FK-506 is 50 to 100 times more powerful than cyclosporine. Its primary target appears to be the Th lymphocytes, with little effect on other aspects of the immune response. FK-506 acts early in the process of T cell activation and inhibits the production of IL-2. As a result, T lymphocytes do not proliferate, secretion of IFN-γ is inhibited, MHC class II antigens are not induced, and further activation of macrophages does not occur.
Because FK-506 is a more potent immunosuppressant than cyclosporine, patient recovery time is faster. FK-506 has higher toxicity compared with cyclosporine. Nephrotoxicity, hyperkalemia, hypokalemia, hypomagnesemia, hypertension, and other side effects may occur, but FK-506 causes no serious side effects (e.g., kidney damage, elevated blood pressure, mood swings). Patients receiving FK-506 have increased susceptibility to infections (e.g., CMV) and an increased risk of developing lymphoma or posttransplantation lymphoproliferative diseases. Inhibitors and inducers of P-450 3A4 may demonstrate an altered rate of metabolism that requires an adjustment in drug dose.
Sirolimus
Sirolimus (Rapamune), previously referred to as rapamycin, was under development for more than 20 years before gaining approval by the U.S. Food and Drug Administration (FDA). Sirolimus is derived from the fungus Streptomyces hygroscopicus from the soil of Easter Island. Structurally, sirolimus resembles tacrolimus and has the same intracellular binding protein or immunophilin, known as FKBP-12, but sirolimus has a novel mechanism of action. Sirolimus is a substrate for P-450 3A4 and inhibits the activation and proliferation of T lymphocytes and subsequent production of IL-2, IL-4, and IL-15. Sirolimus also inhibits antibody production. Sirolimus has been approved as an adjunctive agent (in combination with steroids) for the prevention of acute renal allograft rejection. The main side effects include increased risk of infections and lymphoma, hypercholesterolemia, hypertriglyceridemia, interstitial pneumonitis, insomnia and tremor, and thrombocytopenia.
Mycophenolate Mofetil
Mycophenolate mofetil (RS-61443) inhibits de novo guanosine synthesis by inhibiting inosine monophosphate dehydrogenase. This drug inhibits T and B lymphocyte proliferation and antibody formation by B lymphocytes and has been efficacious as prophylactic and rescue therapy in refractory renal allograft rejection in clinical trials.
Mycophenolate mofetil (MMF; CellCept), is a drug that is now being used more frequently in treatment plans as a substitute for azathioprine. MMF prevents the production of cells such as azathioprine but is believed to be more effective for preventing rejection in patients. Studies have suggested that mycophenolate is effective in preventing acute rejection and may also slow the progression to chronic rejection. Adverse side effects include a lowering in blood cell development, which can cause abdominal pain, vomiting, and diarrhea, but generally it is a well-tolerated drug.
Antilymphocyte (Antithymocyte) Globulin
Other immunosuppressive measures directed at T cells include the use of antilymphocyte (antithymocyte) globulin (ATG), an IgG polyclonal antibody, at the time of transplantation and the use of lymphoid irradiation before transplantation. The useful ness of ATG for preventing or reversing rejection in renal allograft recipients has been well established. Adverse side effects can include complement-mediated lysis of lymphocytes, serum sickness, leukopenia, and thrombocytopenia.
Among patients at high risk for acute rejection or delayed graft function who have received a kidney transplant from a cadaveric donor, induction therapy consisting of a 5-day course of antithymocyte globulin, as compared with basiliximab, reduces the incidence and severity of acute rejection but not the incidence of delayed graft function.
A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic cell transplantation.
Nulojix
One of the newest drugs is Nulojix (belatacept). This drug was approved by the FDA in 2011 to prevent acute rejection in adult patients who have had a kidney transplant. This drug is approved for use with other immunosuppressants, e.g., basiliximab, mycophenolate mofetil, and corticosteroids. This type of drug is called a selective T cell costimulation blocker.
Monoclonal Antibodies
Monoclonal antibody (muromonab-CD3, OKT2 [Ortho clone, OKT3]) is used because the CD3 surface membrane marker is found on all mature post-thymic T cells. Interaction between OKT3 and the surface of mature T lymphocytes causes T cell depletion. The use of OKT3 reverses almost all acute renal transplant rejection and is indicated for the treatment of steroid-resistant rejection. A side effect of this drug is cytokine-release syndrome, a condition of flulike symptoms, dyspnea, aseptic meningitis, and pulmonary edema.
Dacliximab (Zenapax) is a recently approved humanized monoclonal antibody to the alpha subunit of the IL-2 receptor. A decreased incidence of renal allograft rejection has been observed with triple- and/or double-immunosuppressive regimens.
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