- Immunosuppressive drug
:"For a list of immunosuppressive drugs, see the
Immunosuppressive drugs, immunosuppressive agents, or immunosuppressants are drugs that inhibit or prevent activity of the
immune system. They are used in immunosuppressive therapy to:
* Prevent the rejection of transplanted organs and tissues (e.g.,
bone marrow, heart, kidney, liver)
* Treat autoimmune diseases or diseases that are most likely of autoimmune origin (e.g.,
rheumatoid arthritis, multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, Crohn's disease, pemphigus, and ulcerative colitis).
* Treat some other non-autoimmune inflammatory diseases (e.g., long term allergic
These drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune system is less able to resist
infections and the spread of malignant cells. There are also other side-effects, such as hypertension, dyslipidemia, hyperglycemia, peptic ulcers, liver, and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolismand action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects on lymphocytesubpopulations in tissues using immunohistochemistry.cite journal | author=N A Gillett and C Chan | title=Applications of immunohistochemistry in the evaluation of immunosuppressive agents | journal=Human & Experimental Toxicology | volume=19 | issue=4 | pages=251–254 | year=2000 | doi=10.1191/096032700678815819]
Immunosuppressive drugs can be classified into five groups:
* drugs acting on immunophilins
* other drugs.
In pharmacologic (supraphysiologic) doses, glucocorticoids are used to suppress various allergic, inflammatory, and autoimmune disorders. They are also administered as posttransplantory immunosuppressants to prevent the acute transplant rejection and
graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes.
Glucocorticoids suppress the
cell-mediated immunity. They act by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-γ, the most important of which is the IL-2. Smaller cytokineproduction reduces the T cellproliferation.
Glucocorticoids also suppress the
humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibodysynthesis.
Glucocorticoids influence all types of inflammatory events, no matter what their cause. They induce the
lipocortin-1(annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoidproduction. The cyclooxygenase(both COX-1 and COX-2) expression is also suppressed, potentiating the effect.
Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the
leukocytemembrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines, etc.) from neutrophils, macrophages, and mastocytes.
Chemotherapy" Cytostatics inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purineanalogs are most frequently administered.
The alkylating agents used in immunotherapy are nitrogen mustards (
cyclophosphamide), nitrosoureas, platinumcompounds, and others. Cyclophosphamide is probably the most potent immunosuppressive compound. In small doses, it is very efficient in the therapy of systemic lupus erythematosus, autoimmune hemolytic anemias, Wegener's granulomatosis, and other immune diseases. High doses cause pancytopeniaand hemorrhagic cystitis.
Antimetabolites interfere with the synthesis of nucleic acids. These include:
folic acidanalogues, such as methotrexate
purineanalogues such as azathioprineand mercaptopurine
*protein synthesis inhibitors.
Methotrexateis a folic acidanalogue. It binds dihydrofolate reductaseand prevents synthesis of tetrahydrofolate. It is used in the treatment of autoimmune diseases (for example rheumatoid arthritis) and in transplantations.
Azathioprine and Mercaptopurine
Azathioprine, is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant rejection reactions. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing the clonal expansion of
lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases.
dactinomycinis the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin.
Antibodies are used as a quick and potent immunosuppression method to prevent the acute rejection reaction.
polyclonal antibodiesare obtained from the serum of animals (e.g., rabbit, horse), and injected with the patient's thymocytes or lymphocytes. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and grave aplastic anemiatreatment. However, they are added primarily to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporine therapy. Polyclonal antibodiesinhibit T lymphocytes and cause their lysis, which is both complement-mediated cytolysis and cell-mediated opsonizationfollowed by removal of reticuloendothelial cells from the circulation in the spleenand liver] . In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including graft rejection, delayed hypersensitivity (i.e., tuberculin skin reaction), and the graft-versus-host disease(GVHD), but influence thymus-dependentantibody production.
March 2005, there are two preparations available to the market: Atgam (R), obtained from horse serum, and Thymoglobuline (R), obtained from rabbit serum. Polyclonal antibodies affect all lymphocytes and cause general immunosuppression, possibly leading to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially by cytomegalovirus. To reduce these risks, treatment is provided in a hospital, where adequate isolation from infection is available. They are usually administered for five days intravenously in the appropriate quantity. Patients stay in the hospital as long as three weeks to give the immune system time to recover to a point where there is no longer a risk of serum sickness.
Because of a high
immunogenicityof polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized by fever, rigorepisodes, and even anaphylaxis. Later during the treatment, some patients develop serum sickness or immune complex glomerulonephritis. Serum sickness arises seven to fourteen days after the therapy has begun. The patient suffers from fever, joint pain, and erythemathat can be soothed with the use of steroids and analgesics. Urticaria(hives) can also be present. It is possible to diminish their toxicity by using highly-purified serum fractions and intravenous administration in the combination with other immunosuppressants, for example, calcineurin inhibitors, cytostatics and cortisteroids. The most frequent combination is to use antibodies and cyclosporine simultaneously in order to prevent patients from gradually developing a strong immune response to these drugs, reducing or eliminating their effectiveness.
Monoclonal antibodiesare directed towards exactly defined antigens. Therefore, they cause fewer side-effects. Especially significant are the IL-2 receptor- (CD25-) and CD3-directed antibodies. They are used to prevent the rejection of transplanted organs, but also to track changes in the lymphocyte subpopulations. It is reasonable to expect similar new drugs in the future.
T-cell receptor directed antibodies
As of 2007
OKT3(also called muromab) is the only approved anti-CD3 antibody. It is a murine anti-CD3 monoclonal antibody of the IgG2a type that prevents T-cellactivation and proliferation by binding the T-cell receptor complex present on all differentiated T cells. As such it is one of the most potent immunosuppressive substances and is administered to control the steroid- and/or polyclonal antibodies-resistant acute rejection episodes. As it acts more specifically than polyclonal antibodies it is also used prophylactically in transplantations.
At present the OKT3's mechanism of action is only partially understood. It is known that the molecule binds TCR/CD3 receptor complex. In the first few administrations this binding non-specifically activates T-cells, leading to a serious syndrome 30 to 60 minutes later. It is characterized by fever,
myalgia, headache, and arthralgia. Sometimes it develops in a life-threatening reaction of the cardiovascular system and the central nervous system, requiring a lengthy therapy. Past this period CD3 (R) blocks the TCR-antigen binding and causes conformational changeor the removal of the entire TCR3/CD3 complex from the T-cell surface. This lowers the number of available T-cells, perhaps by sensitizing them for the uptake by the epithelial reticular cells. The cross-binding of CD3 molecules as well activates an intracellular signal causing the T cell anergy or apoptosis, unless the cells receive another signal through a co-stimulatory molecule. CD3 antibodies shift the balance from Th1 to Th2 cells.
When deciding to include OKT3 in the treatment a healthcare practitioner must consider not only its great efficiency but also its toxic side-effects. The risk of excessive immunosuppression and the risk of development of neutralizing antibodies could make it inefficacious. Although CD3 antibodies act more specifically than polyclonal antibodies, they lower the cell-mediated immunity significantly, predisposing the patient to
opportunistic infections and malignancies.
IL-2 receptor directed antibodies
Interleukin-2is an important immune system regulator necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface receptor IL-2a, consisting of the α, β, and γ chains. The IL-2a (CD25, T-cell activation antigen, TAC) is expressed only by the already-activated T lymphocytes. Therefore, it is of special significance to the selective immunosuppressive treatment, and the research has been focused on the development of effective and safe anti-IL-2 antibodies. By the use of the recombinant gene technology, the mouse anti-Tac antibodies have been modified, leading to the presentation of two himeric mouse/human anti-Tac antibodies in the year 1998: basiliximab (Simulect (R)) and daclizumab (Zenapax (R)). These drugs act by binding the IL-2a receptor's α chain, preventing the IL-2 induced clonal expansion of activated lymphocytes and shortening their survival. They are used in the prophylaxis of the acute organ rejection after the bilateral kidney transplantation, both being similarly effective and with only few side-effects.
Drugs acting on immunophilins
tacrolimus, cyclosporinis a calcineurininhibitor. It has been in use since 1983and is one of the most-widely-used immunosuppressive drugs. It is a fungal peptide, composed of 11 amino acids.
Cyclosporin is thought to bind to the cytosolic protein
cyclophilin(an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normal circumstances induces the transcription of interleukin-2. The drug also inhibits lymphokineproduction and interleukinrelease, leading to a reduced function of effector T-cells.
Cyclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is
Tacrolimus (Prograf(TM), FK506)
Tacrolimusis a fungal product (" Streptomyces tsukubaensis"). It is a macrolide lactoneand acts by inhibiting calcineurin.
The drug is used particularly in the liver and kidney transplantations, although in some clinics it is used in heart, lung and heart/lung transplants. It binds to an
immunophilin, followed by the binding of the complex to calcineurinand the inhibition of its phosphataseactivity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than cyclosporin and has less-pronounced side-effects.
irolimus (Rapamune (Tm), Rapamycin)
Sirolimusis a macrolide lactone, produced by the actinomycetes " Streptomyces hygroscopicus". It is used to prevent rejection reactions. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side-effects.
Contrary to cyclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation. It binds to the same receptor (immunophilin) as tacrolimus, however the produced complex does not inhibit calcineurin, but another protein. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side-effects. Also, it indirectly inhibits several T lymphocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. In a similar manner, it prevents the B cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG, and IgA antibodies produced. It acts as an immunoregulatory agent, and is also active against tumors that involve the PI3K/AKT/mTOR pathway.
IFN-β suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression of
multiple sclerosis. IFN-γ is able to trigger lymphocytic apoptosis.
Prolonged use of
opioids may cause immunosuppression of both innate and adaptive immunity.cite journal | author=S Roy and HH Loh | title=Effects of opioids on the immune system | journal=Neurochem Res. | volume=21 | issue=11 | pages=1375–1386 | pmid=8947928 | doi=10.1007/BF02532379 | year=1996] Decrease in proliferation as well as immune function has been observed in macrophages, as well as lymphocytes. It is thought that these effects are mediated by opioid receptors expressed on the surface of these immune cells.
TNF binding proteins
TNF-α- (tumor necrosis factor-alpha-) binding protein is a monoclonal antibody or a circulating receptor such as infliximab(Remicade), etanercept(Embrel), or adalimumab(Humira) that binds to TNF-α, preventing it from inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte-activating molecules. They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis.
TNF or the effects of TNF are also suppressed by various natural compounds, including
curcumin(an ingredient in turmeric) and catechins (in green tea).
These drugs may raise the risk of contracting
tuberculosisor inducing a latent infection to become active. Infliximab and adalimumab have label warnings stating that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with them.
Mycophenolic acidacts as a non-competitive, selective, and reversible inhibitor of Inosine-5′-monophosphate dehydrogenase(IMPDH), which is a key enzyme in the "de novo" guanosinenucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process.
mall biological agents
FTY720is a new synthetic immunosuppressant, currently in phase 3 of clinical trials. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes, so they accumulate in the lymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants. Myriocinhas been reported being 10 to 100 times more potent than Cyclosporin
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