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Immunosuppressive drugs, also known asimmunosuppressive agents,immunosuppressants andantirejection medications, aredrugs that inhibit or prevent the activity of theimmune system.
Immunosuppressive drugs can be classified into five groups:[citation needed]
In pharmacologic (supraphysiologic) doses, glucocorticoids, such asprednisone,dexamethasone, andhydrocortisone are used to suppress variousallergic,inflammatory, and autoimmune disorders. They are also administered as posttransplantory immunosuppressants to prevent theacute transplant rejection andgraft-versus-host disease. Nevertheless, they do not prevent an infection and also inhibit laterreparative processes.
Glucocorticoids suppresscell-mediated immunity. They act by inhibitinggene expression of cytokines includingInterleukin 1 (IL-1),IL-2,IL-3,IL-4,IL-5,IL-6,IL-8, and TNF-alpha by binding to corticosteroidresponse elements on DNA.[1] This decrease incytokine production reducesT cell proliferation. With decreased T cell proliferation there is decreased production of IL-2. This further decreases the proliferation of T cells.[2][3]
Glucocorticoids also suppress thehumoral immunity, causingB cells to express smaller amounts of IL-2 andIL-2 receptors. This diminishes both B cell clone expansion andantibody synthesis.
Glucocorticoids influence all types of inflammatory events, no matter their cause. They induce thelipocortin-1 (annexin-1) synthesis, which then binds tocell membranes preventing thephospholipase A2 from coming into contact with itssubstratearachidonic acid. This leads to diminishedeicosanoid production. Thecyclooxygenase (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 theleukocyte membrane receptors and inhibits various inflammatory events:epithelialadhesion,emigration,chemotaxis,phagocytosis,respiratory burst, and the release of various inflammatory mediators (lysosomal enzymes, cytokines,tissue plasminogen activator,chemokines, etc.) fromneutrophils,macrophages, andmastocytes.
Cytostatics inhibitcell 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,purine analogs are most frequently administered.
Thealkylating agents used in immunotherapy arenitrogen mustards (cyclophosphamide),nitrosoureas,platinum compounds, and others. Cyclophosphamide (Baxter's Cytoxan) is probably the most potent immunosuppressive compound. In small doses, it is very efficient in the therapy ofsystemic lupus erythematosus, autoimmunehemolytic anemias,granulomatosis with polyangiitis, and other immune diseases. High doses causepancytopenia and hemorrhagiccystitis.
Antimetabolites interfere with the synthesis of nucleic acids. These include:
Methotrexate is afolic acid analogue. It bindsdihydrofolate reductase and prevents synthesis oftetrahydrofolate. It is used in the treatment of autoimmune diseases (for example rheumatoid arthritis or Behcet's Disease) and in transplantations.
Azathioprine (Prometheus' Imuran), is the main immunosuppressive cytotoxic substance. It is extensively used to control transplant rejection reactions. It is nonenzymatically cleaved tomercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing the clonal expansion oflymphocytes in the induction phase of the immune response, it affects both thecell and thehumoral immunity. It is also efficient in the treatment of autoimmune diseases.
Among these,dactinomycin is the most important. It is used inkidney transplantations. Other cytotoxic antibiotics areanthracyclines,mitomycin C,bleomycin,mithramycin.
Antibodies are sometimes used as a quick and potent immunosuppressive therapy to prevent the acute rejection reactions as well as a targeted treatment of lymphoproliferative or autoimmune disorders (e.g., anti-CD20 monoclonals).
Heterologouspolyclonal antibodies are obtained from theserum of animals (e.g.,rabbit,horse), and injected with the patient'sthymocytes or lymphocytes. The antilymphocyte (ALG) and antithymocyteantigens (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and graveaplastic anemia treatment. However, they are added primarily to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporin therapy.
Polyclonal antibodies inhibit T lymphocytes and cause theirlysis, which is bothcomplement-mediated cytolysis and cell-mediatedopsonization followed by removal ofreticuloendothelial cells from thecirculation in thespleen andliver. In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including graft rejection,delayed hypersensitivity (i.e.,tuberculin skin reaction), and thegraft-versus-host disease (GVHD), but influencethymus-dependent antibody production.
As of March 2005, there are two preparations available to the market:Atgam, obtained from horse serum, andThymoglobuline, obtained from rabbit serum. Polyclonal antibodies affect all lymphocytes and cause general immunosuppression, possibly leading topost-transplant lymphoproliferative disorders (PTLD) or serious infections, especially bycytomegalovirus. 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 ofserum sickness.
Because of a highimmunogenicity of polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized byfever,rigor episodes, and evenanaphylaxis. Later during the treatment, some patients develop serum sickness orimmune complex glomerulonephritis. Serum sickness arises seven to fourteen days after the therapy has begun. The patient has fever,joint pain, anderythema that can be soothed with the use of steroids andanalgesics.Urticaria (hives) can also be present. It is possible to diminish their toxicity by using highly purifiedserum fractions and intravenous administration in the combination with other immunosuppressants, for example,calcineurin inhibitors, cytostatics, andcorticosteroids. The most frequent combination is to use antibodies and ciclosporin simultaneously in order to prevent patients from gradually developing a strong immune response to these drugs, reducing or eliminating their effectiveness.
Monoclonal antibodies are directed towards exactly defined antigens. Therefore, they cause fewer side-effects. Especially significant are theIL-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.
Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type that was previously used to preventT-cell activation and proliferation by binding the T-cell receptor complex present on all differentiated T cells. As such it was one of the first potent immunosuppressive substances and was administered to control the steroid- and/or polyclonal antibodies-resistant acute rejection episodes. As it acts more specifically than polyclonal antibodies it was also used prophylactically in transplantations. However, muromonab-CD3 is no longer produced,[4] and this mouse monoclonal antibody has been replaced in the clinic with chimeric, humanized, or human monoclonal antibodies.
The muromonab'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, andarthralgia. 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 blocks the TCR-antigen binding and causesconformational change or 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 theepithelial 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 aco-stimulatory molecule. CD3 antibodies shift the balance fromTh1 toTh2 cells as CD3 stimulates Th1 activation.[5]
The patient may developneutralizing antibodies reducing the effectiveness of muromonab-CD3.Muromonab-CD3 can cause excessive immunosuppression. Although CD3 antibodies act more specifically than polyclonal antibodies, they lower the cell-mediated immunity significantly, predisposing the patient toopportunistic infections and malignancies.[6]
Interleukin-2 is an important immune system regulator necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surfacereceptor 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 research has been focused on the development of effective and safe anti-IL-2 antibodies. By the use ofrecombinant gene technology, the mouse anti-Tac antibodies have been modified, leading to the presentation of two chimeric mouse/human anti-Tac antibodies in the year 1998:basiliximab (Simulect) anddaclizumab (Zenapax). 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 bilateralkidney transplantation, both being similarly effective and with only few side-effects.[citation needed]
Liketacrolimus, ciclosporin (Novartis' Sandimmune) is acalcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs. It is a cyclic fungal peptide, composed of 11 amino acids.
Ciclosporin is thought to bind to the cytosolic proteincyclophilin (animmunophilin) of immunocompetent lymphocytes, especiallyT-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatasecalcineurin, which under normal circumstances induces the transcription ofinterleukin-2. The drug also inhibitslymphokine production andinterleukin release, leading to a reduced function of effector T-cells.
Ciclosporin is used in the treatment of acute rejection reactions, but has been increasingly substituted with newer, and lessnephrotoxic,[7] immunosuppressants.
Calcineurin inhibitors and azathioprine have been linked with post-transplant malignancies andskin cancers in organ transplant recipients.Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. The results of several studies suggest that calcineurin inhibitors have oncogenic properties mainly linked to the production of cytokines that promote tumor growth, metastasis and angiogenesis.
This drug has been reported to reduce the frequency ofregulatory T cells (T-Reg) and after converting from a CNI monotherapy to amycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.[8]
Tacrolimus (trade names Prograf, Astagraf XL, Envarsus XR) is a product of the bacteriumStreptomyces tsukubensis. It is amacrolide lactone and acts by inhibitingcalcineurin.
The drug is used primarily in liver and kidney transplantations, although in some clinics it is used in heart, lung, and heart/lung transplantations. It binds to the immunophilinFKBP1A, followed by the binding of the complex tocalcineurin and the inhibition of itsphosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of thecell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.
Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone, produced by theactinomycete bacteriumStreptomyces 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 ciclosporin and tacrolimus, drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second phase, namely signal transduction and lymphocyte clonal proliferation. It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein,mTOR. Therefore, sirolimus acts synergistically with ciclosporin and, in combination with other immunosuppressants, has few side effects. Also, it indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle. In a similar manner, Sirolimus prevents B cell differentiation into plasma cells, reducing production of IgM, IgG, and IgA antibodies.
It is also active againsttumors that are PI3K/AKT/mTOR-dependent.
Everolimus is an analog of sirolimus and also is an mTOR inhibitor.
Zotarolimus is a semi-synthetic derivative of sirolimus used indrug-eluting stents.
IFN-β suppresses the production of Th1 cytokines and the activation of monocytes. It is used to slow down the progression ofmultiple sclerosis. IFN-γ is able to trigger lymphocyticapoptosis.
Prolonged use ofopioids may cause immunosuppression of both innate and adaptive immunity.[9] 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.[9]
ATNF-α (tumor necrosis factor-alpha) binding protein is a monoclonal antibody or a circulatingreceptor such asinfliximab (Remicade),etanercept (Enbrel), oradalimumab (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 ofrheumatoid arthritis,ankylosing spondylitis,Crohn's disease, andpsoriasis.
These drugs may raise the risk of contractingtuberculosis or 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.
TNF or the effects of TNF are also suppressed by various natural compounds, includingcurcumin (an ingredient inturmeric) and catechins (ingreen tea).
Mycophenolic acid acts as a non-competitive, selective, and reversible inhibitor ofinosine-5′-monophosphate dehydrogenase (IMPDH), which is a key enzyme in thede novoguanosine nucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process. Mycophenolate mofetil is used in combination with ciclosporin or tacrolimus in transplant patients.
Fingolimod is a synthetic immunosuppressant. It increases the expression or changes the function of certain adhesion molecules (α4/β7integrin) in lymphocytes, so they accumulate in thelymphatic tissue (lymphatic nodes) and their number in the circulation is diminished. In this respect, it differs from all other known immunosuppressants.
Myriocin has been reported being 10 to 100 times more potent thanCiclosporin.
Immunosuppressive drugs are used inimmunosuppressive therapy to:
A commonside-effect of many immunosuppressive drugs isimmunodeficiency, because the majority of them act non-selectively, resulting in increased susceptibility toinfections, decreasedcancer immunosurveillance and decreased ability to produce antibodies aftervaccination.[10][11]However, the vaccination status of patients taking immunosuppressive drugs for chronic diseases such asRheumatoid arthritis orInflammatory bowel disease should be investigated before starting any treatment, and patients should eventually be vaccinated againstVaccine-preventable disease.[12] Some studies showed a low vaccination rate against someVaccine-preventable disease among patients taking immunosuppressive drugs, despite a generally positive attitude towards vaccinations.[13]
There are also other side-effects, such ashypertension,dyslipidemia,hyperglycemia,peptic ulcers,lipodystrophy,moon face,liver injury andkidney injury. The immunosuppressive drugs also interact with other medicines and affect theirmetabolism and action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects onlymphocyte subpopulations in tissues usingimmunohistochemistry.[14]
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