Immunosuppressive drug

For a list of immunosuppressive drugs, see the transplant rejectionpage.

Immunosuppressive drugs or immunosuppressants are drugsthat are used in immunosuppressive therapyto inhibit or prevent activity of the immune system. Clinically they are used to:

• prevent the rejectionof transplantedorgans and tissues (e.g. bone marrow, heart, kidney, liver)
• treatment of autoimmune diseasesor diseases that are most likely of autoimmune origin (e.g. rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus, ulcerative colitis).

These drugs are not without side effectsand risks. Because the majority of them act non-selectively, the immune system loses its ability to successfully resist infectionsand spreading of malignant cells. There are also other side effects, like hypertension, dyslipidemia, hyperglycemia, peptic ulcers, liver and kidney injury. The immunosuppressive drugs also interact with other medicines and affect their metabolismand action.

Immunosuppressive drugs can be classified into four groups:

• glucocorticoids
• cytostatics
• antibodies
• drugs acting on immunophilins
• other drugs

Glucocorticoids

General information: Glucocorticoid.

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 rejectionand graft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit later reparative processes.

Immunosuppressive mechanism

Glucocorticoids suppress the cell-mediated immunity. They act by inhibitinggenes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8and 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 cellsto express smaller amounts of IL-2 and of IL-2 receptors. This diminishes both B cell clone expansion and antibodysynthesis.

Antiinflammatory effects

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 membranespreventing the phospholipase A2from coming into contact with its substratearachidonic 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: epithelialadhesion, emigration, chemotaxis, phagocytosis, respiratory burstand the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokinesetc.) from neutrophils, macrophagesand mastocytes.

Cytostatics

General information: Chemotherapy

Cytostatics inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malign diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purineanalogs are most frequently administered.

Alkylating agents

The alkylating agentsused 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 granulomatosisand other immune diseases. High doses cause pancytopeniaand hemorrhagic cystitis.

Antimetabolites

Main representatives of antimetabolitesare folic acidanalogues (methotrexate), purineanalogues (azathioprine, mercaptopurine), pyrimidineanalogues, protein synthesisinhibitors. They interfere with the synthesis of nucleic acids.

Methotrexate

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

Azathioprine, is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant rejection reactions. It is nonenzymatically cleaved to 6-mercaptopurine that acts as a purine analogue and an inhibitor of DNA synthesis. By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the celland the humoral immunity. It is also efficient in the treatment of autoimmune diseases.

Cytotoxic antibiotics

Among these, dactinomycinis the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mitramycin.

Antibodies

Antibodiesare used as a quick and potent immunosuppression method to prevent the acute rejection reaction.

Polyclonal antibodies

Heterologous polyclonal antibodiesare obtained from the serumof different animals (e.g. rabbit, horse) injected with patient's thymocytesor 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 primarily added to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporine therapy. They are usually administered for five days intravenously in the appropriate quantity. Patient stays in the hospital for three weeks so the immune system recovers and there is no risk of serum sicknessanymore.

Polyclonal antibodies inhibit T lymphocytes and cause their lysis, which is both complementmediated cytolysis and cell-mediated opsonizationfollowed by removal of reticuloendothelial cellsfrom the circulationin 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.

Currently (March 2005) there are two preparations available to the market: Atgam (R), obtained from the horse serum, and Thymoglobuline (R), obtained from the 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 prevent this, the therapy must obligatorily be performed in a hospital, where adequate isolation from infection is available.

Because of a high immunogenicityof polyclonal antibodies, almost all patients develop an acute reaction develop at first. 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 painand erythemathat can be soothed with the use of steroids and analgesics. Urticaria(hives) can also be present. Patients also gradually develop a strong immune response against these drugs, so they stop to be effective. It is possible to diminish their toxicity by using highly purified serum fractionsand intravenous administration in the combination with other immunosuppressants, for example calcineurin inhibitors, cytostatics and cortisteroids. The most frequent combination is to simultaneously use antibodies and cyclosporine.

Monoclonal antibodies

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

OKT3 (R) is presently the only approved anti-CD3 antibody. It is a mouse 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 clinically used to control the steroid and/or polyclonal antibodies resistant acute rejection episodes. For acting more specifically than polyclonal antibodies, it is also used preventively in transplantations.

Presently, the OKT3's action mechanism is not yet sufficiently understood. It is known that the molecule binds TCR/CD3, the T-cell receptor complex. During 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 artralgia. In some cases, it progresses to a life-threatening reaction of the cardiovascular system and the central nervous system needing a lengthy therapy. Past this period, CD3 (R) blocks the TCR - antigen binding and causes conformation change or the removal of the entire TCR3/CD3 from the T-cell surface. This lowers the number of T cells, perhaps by sensitising them for the uptake by the reticular epithelial cells. The cross-binding of CD3 molecules also activates an intracellular signal, causing the T cells' anergy or apoptosis, unless they receive another signal through a costimulatory molecule. CD3 antibodies also shift the balance from Th1 to Th2 cells.

Deciding whether to use OKT3(R) in the treatment, it is therefore necessary not only to consider its great effectiveness, but also its toxic side effects: the risk of excessive immunosuppression and the risk that the patient develops neutralizing antibodies against the drug, making it inefficacious. Although CD3(R) 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 profilaxis of the acute organ rejection after the bilateral kidney transplantation, both being similarly effective and with only few side effects.

Drugs acting on immunophilins

Cyclosporine

General information:cyclosporine

Together with tacrolimus, cyclosporineis 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.

Cyclosporine is thought to bind to the cytosolic protein cyclophilin(an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophylin 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.

Cyclosporine is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer immunosuppressants, as it is nephrotoxic.

Tacrolimus (Prograf(TM), FK506)

Tacrolimusis a fungal product (Streptomyces tsukubaensis) too. 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 calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the passage of G0 into G1 phase. Tacrolimus is more potent than cyclosporine and has less pronounced side effects.

Sirolimus (Rapamune (Tm), Rapamicin)

Sirolimusis a macrolide lactone, produced by the actinomycetesStreptomyces 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. Indirectly it inhibits several T lympohocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. Similarly, it prevents the B cell differentiation to the plasma cells, which lowers the quantity of IgM, IgG and IgA antibodies produced. It acts immunoregulatory.

Other drugs

Interferons

General information:Interferon.

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.

Opioids

Prolonged use of opioidsmay cause immunosuppression by inhibiting the migration of leukocytes.

TNF binding proteins

A TNF-α (tumor necrosis factor alpha) binding protein is a monoclonal antibody or a circulating receptorsuch as infliximab(Remicade®), etanercept(Enbrel®), or adalimumab (Humira®) that binds to TNF-α and prevent 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 diseaseand 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.

Mycophenolate mofetil

Mycophenolate mofetilacts as a non-competitive, selective and reversible inhibitor of inosine 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.

Small 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.

External links

• Pancreas-Kidney Transplantation: Drugs, a brief history of immunosuppressive drugs. Accessed on 21 August 2005.
• WSAVA 2001 - Immunosuppressive drug therapy, from the veterinary point of view. By Mark Papich. Accessed on 21 August 2005.
• Newer Immunosuppressive Drugs;A Review-Gummert et al. - J Am Soc Nephrol 10:1366-1380, 1999. Free full text at JASN. Accessed on 21 August 2005.
• Principles and Practice of Monitoring Immunosuppressive Drugs. W.V.Armstrong, J Lab Med, 2002, 26 (1/2): 27-36. PDF. Accessed on 21 August 2005.
• Are Immunosuppressive Drugs a Useful Adjuvant to Treatment of HIV with Antiretrovirals?. Hivandhepatitis.com. Accessed on 21 August 2005.
• Immunosuppression. By Randy P Prescilla, MD; accessed on Emedicine.com on 21 August 2005
• National Kidney Foundation: A to Z Health Guide, answers to some frequently asked questions about immunosuppression in renal transplatation for a layman. Accessed on 21 August 2005.
• Immunosuppressants, Pharmacologic profile. Drugguide.com. Accessed on 21 August 2005.
• Immunosuppressants, a collection of links at About.com. Accessed ob 21 August 2005.fr:Immunosuppresseur

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It uses material from the http://en.wikipedia.org/wiki/Immunosuppressive+drug Wikipedia article Immunosuppressive drug.