Immunosuppressive drug 249958 224769093 2008-07-10T09:55:18Z Brianpie 1286936 Link to spanish page :''For a list of immunosuppressive drugs, see the [[transplant rejection]] page''. '''Immunosuppressive drugs''', '''immunosuppressive agents''', or '''immunosuppressants''' are [[medication|drugs]] that inhibit or prevent activity of the [[immune system]]. They are used in [[immunosuppression|immunosuppressive therapy]] to: * Prevent the [[transplant rejection|rejection]] of [[Organ transplant|transplanted]] organs and tissues (e.g., [[bone marrow]], [[heart]], [[kidney]], [[liver]]) * Treat [[autoimmunity|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 [[asthma]] control). These drugs are not without [[Adverse effect (medicine)|side-effects]] and risks. Because the majority of them act non-selectively, the immune system is less able to resist [[infection]]s and the spread of [[cancer|malignant cells]]. There are also other side-effects, such as [[arterial hypertension|hypertension]], [[dyslipidemia]], [[hyperglycemia]], [[peptic ulcer]]s, [[Hepatotoxicity|liver]], and [[Nephrotoxicity|kidney injury]]. The immunosuppressive drugs also interact with other medicines and affect their [[metabolism]] and action. Actual or suspected immunosuppressive agents can be evaluated in terms of their effects on [[lymphocyte]] subpopulations in tissues using [[immunohistochemistry]].<ref name="">{{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}}</ref> Immunosuppressive drugs can be classified into five groups: * [[#Glucocorticoids|glucocorticoid]]s * [[#Cytostatics|cytostatic]]s * [[#Antibodies|antibodies]] * [[#Drugs acting on immunophilins|drugs acting on immunophilin]]s * [[#Other drugs|other drugs]]. {{TOClimit|limit=3}} ==Glucocorticoids== ''General information: [[Glucocorticoid]].'' In pharmacologic (supraphysiologic) doses, glucocorticoids are used to suppress various [[allergy|allergic]], [[inflammation|inflammatory]], and autoimmune disorders. They are also administered as posttransplantory immunosuppressants to prevent the [[transplant rejection|acute transplant rejection]] and [[graft-versus-host disease]]. Nevertheless, they do not prevent an infection and also inhibit later [[tissue reparation|reparative processes]]. ===Immunosuppressive mechanism=== Glucocorticoids suppress the [[cell-mediated immunity]]. They act by inhibiting genes that code for the cytokines [[IL-1]], [[Interleukin 2|IL-2]], [[IL-3]], [[Interleukin 4|IL-4]], [[IL-5]], [[Interleukin 6|IL-6]], [[IL-8]], and TNF-γ, the most important of which is the IL-2. Smaller [[cytokine]] production reduces the [[T cell]] proliferation. Glucocorticoids also suppress the [[humoral immunity]], causing [[B cell]]s to express smaller amounts of IL-2 and [[IL-2 receptor]]s. This diminishes both B cell clone expansion and [[antibody]] synthesis. ===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 membrane]]s preventing the [[phospholipase A2]] from coming into contact with its [[substrate (biochemistry)|substrate]] [[arachidonic acid]]. This leads to diminished [[eicosanoid]] production. 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 [[leukocyte]] membrane receptors and inhibits various inflammatory events: [[epithelium|epithelial]] [[cell adhesion|adhesion]], [[emigration]], [[chemotaxis]], [[phagocytosis]], [[respiratory burst]], and the release of various inflammatory mediators (lysosomal enzymes, cytokines, [[tissue plasminogen activator]], [[chemokine]]s, etc.) from [[neutrophil]]s, [[macrophage]]s, and [[mastocyte]]s. ==Cytostatics== ''General information: [[Chemotherapy]]'' [[Cytostatic]]s 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, [[purine]] analogs are most frequently administered. ====Alkylating agents==== The [[alkylating antineoplastic agent|alkylating agent]]s used in immunotherapy are [[mustard gas|nitrogen mustards]] ([[cyclophosphamide]]), [[nitrosourea]]s, [[platinum]] compounds, 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 [[hemolysis#hemolytic anemia|hemolytic anemias]], [[Wegener's granulomatosis]], and other immune diseases. High doses cause [[pancytopenia]] and hemorrhagic [[cystitis]]. ====Antimetabolites==== [[Antimetabolite]]s interfere with the synthesis of nucleic acids. These include: *[[folic acid]] analogues, such as [[methotrexate]] *[[purine]] analogues such as [[azathioprine]] and [[mercaptopurine]] *[[pyrimidine]] analogues *[[protein biosynthesis|protein synthesis]] inhibitors. =====Methotrexate===== [[Methotrexate]] is a [[folic acid]] analogue. It binds [[dihydrofolate reductase]] and prevents synthesis of [[folic acid#biochemistry|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 [[lymphocyte]]s in the induction phase of the immune response, it affects both the [[cell immunity|cell]] and the [[humoral immunity]]. It is also efficient in the treatment of autoimmune diseases. ====Cytotoxic antibiotics==== Among these, [[dactinomycin]] is the most important. It is used in [[kidney transplantation]]s. Other cytotoxic antibiotics are [[anthracycline]]s, [[mitomycin C]], [[bleomycin]], [[mithramycin]]. ==Antibodies== [[Antibody|Antibodies]] are used as a quick and potent immunosuppression method to prevent the acute rejection reaction. ===Polyclonal antibodies=== Heterologous [[polyclonal antibodies]] are obtained from the [[blood plasma|serum]] of animals (e.g., [[rabbit]], [[horse]]), and injected with the patient's [[thymocyte]]s or lymphocytes. The antilymphocyte (ALG) and antithymocyte [[antigen]]s (ATG) are being used. They are part of the steroid-resistant acute rejection reaction and grave [[aplastic anemia]] treatment. However, they are added primarily to other immunosuppressives to diminish their dosage and toxicity. They also allow transition to cyclosporine therapy. [[Polyclonal antibodies]] inhibit T lymphocytes and cause their [[lysis]], which is both [[Complement system|complement]]-mediated cytolysis and cell-mediated [[opsonization]] followed by removal of [[reticuloendothelial cell]]s from the [[circulatory system|circulation]] in the [[spleen]] and liver]]. In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including graft rejection, [[Hypersensitivity#Type IV - cell mediated hypersensitivity|delayed hypersensitivity]] (i.e., [[tuberculin skin reaction]]), and the [[graft-versus-host disease]] (GVHD), but influence [[thymus-dependent]] antibody production. As of [[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 disorder]]s (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 [[immunogenicity]] of polyclonal antibodies, almost all patients have an acute reaction to the treatment. It is characterized by [[fever]], [[rigor]] episodes, 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 [[erythema]] that can be soothed with the use of steroids and [[analgesic]]s. [[Urticaria]] (hives) can also be present. It is possible to diminish their toxicity by using highly-purified [[serum fraction]]s and intravenous administration in the combination with other immunosuppressants, for example, [[#drugs acting on immunophilins|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 antibodies=== [[Monoclonal antibodies]] are 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-cell]] activation 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 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 the [[epithelial reticular cell]]s. 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-stimulation|co-stimulatory molecule]]. CD3 antibodies shift the balance from [[Th1 cell|Th1]] to [[Th2 cell]]s. 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 infection]]s and malignancies. ====IL-2 receptor directed antibodies==== [[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 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== ===Cyclosporin=== ''General information:[[cyclosporin]]'' Together with [[tacrolimus]], [[cyclosporin]] is a [[calcineurin]] inhibitor. It has been in use since [[1983]] and 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 [[lymphokine]] production and [[interleukin]] release, 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 [[nephrotoxic]]. ===Tacrolimus (Prograf(TM), FK506)=== [[Tacrolimus]] is a fungal product (''[[Streptomyces tsukubaensis]]''). It is a [[macrolide lactone]] and 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 cyclosporin and has less-pronounced side-effects. ===Sirolimus (Rapamune (Tm), Rapamycin)=== [[Sirolimus]] is a macrolide lactone, produced by the [[actinomycete]]s ''[[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. ==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 [[opioid]]s may cause immunosuppression of both innate and adaptive immunity.<ref name="royloh">{{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}}</ref> 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.<ref name="royloh"/> ===TNF binding proteins=== A [[TNF]]-α- (tumor necrosis factor-alpha-) binding protein is a monoclonal antibody or a circulating [[receptor (proteomics)|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 [[tuberculosis]] 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. ===Mycophenolate=== [[Mycophenolic acid]] acts as a non-competitive, selective, and reversible inhibitor of [[Inosine-5′-monophosphate dehydrogenase]] (IMPDH), which is a key enzyme in the ''de novo'' [[guanosine]] nucleotide synthesis. In contrast to other human cell types, lymphocytes B and T are very dependent on this process. ===Small biological agents=== [[FTY720]] is 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 system|lymphatic 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 than [[Cyclosporin]] ==References== {{reflist}} ==External links== *[http://www.pancreas-kidney.com/drugs.html Pancreas-Kidney Transplantation: Drugs], a brief history of immunosuppressive drugs. Accessed on 21 August 2005. *[http://www.vin.com/VINDBPub/SearchPB/Proceedings/PR05000/PR00192.htm WSAVA 2001 - Immunosuppressive drug therapy], from the veterinary point of view. By Mark Papich. Accessed on 21 August 2005. *[http://jasn.asnjournals.org/cgi/content/full/10/6/1366 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. *[http://www.degruyter.de/journals/labmed/2002/pdf/26_27.pdf 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. *[http://www.hivandhepatitis.com/recent/immunology/031204.htm Are Immunosuppressive Drugs a Useful Adjuvant to Treatment of HIV with Antiretrovirals?]. Hivandhepatitis.com. Accessed on 21 August 2005. *[http://www.emedicine.com/ped/topic2848.htm Immunosuppression]. By Randy P Prescilla, MD; accessed on Emedicine.com on 21 August 2005 *[http://www.kidney.org/atoz/atozItem.cfm?id=77 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. *[http://www.drugguide.com/classification_articles/immunosuppressants.htm Immunosuppressants, Pharmacologic profile]. Drugguide.com. Accessed on 21 August 2005. *[http://ibscrohns.about.com/od/immunosuppressants/index_r.htm Immunosuppressants], a collection of links at [[About.com]]. Accessed ob 21 August 2005. * {{MeshName|Immunosuppressive+Agents}} {{Major Drug Groups}} {{Immunosuppressants}} [[Category:Immune system]] [[Category:Immunology]] [[Category:Immunosuppressive agents|*]] [[de:Immunsuppressivum]] [[es:Inmunosupresor]] [[fr:Immunosuppresseur]] [[ja:免疫抑制剤]] [[pl:Immunosupresor]] [[ru:Иммуносупрессивные препараты]]