Immunosuppressive drug

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For a list of immunosuppressive drugs, see the transplant rejection page.

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

These drugs are not without side effects and risks. Because mostly they act non-selectively, the immune system is not able to resist successfully to the infections and malignant cells. Other side effects are for example hypertension, dyslipidemia, hyperglycemia, peptic ulcers, liver and kidney damage. The immunosuppressive drugs also interact with other medicines and affect their metabolism and action.

Immunosuppressive drugs can be classified into four groups:

Contents

Glucocorticoids

Main article: Glucocorticoids.

Endogenous glucocorticoids are essential hormones the lack of which is not compatible with life. Their main effects are the maintenance of the appropriate level of glucose in the blood, the maintenance of blood pressure and the prevention of excessive immune response.

Pharmacological or supraphysiological dosages are used in treatment of inflammatory and allergic disorders. They are also used as immunosuppressants after transplantations to prevent the acute transplant rejection by the receiver and also the immune response of the receiver to the receiver's antigens. However, they have many side effects: the gain of body mass, development or aggravation of diabetes, arterial hypertension and/or steroid induced osteoporosis. Therefore, the production of new glucocorticoid remedies is directed to the discovery of selective immunosuppressive drugs.

The mode of action

Glucocorticoids bind to the cytosolic glucocorticoid receptor that is one of the receptors activated after ligand binding. After the hormone binds to the receptor, the receptor-ligand complex is translocated into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of target genes. The DNA bound receptor then interacts with basic transcription factors, which causes the increase in expression of specific target genes. This process is called transactivation. The transactivation mediates most of the main metabolic and cardiovascular side effects.

The mechanism contrary to transactivation is transrepression. Here, the activated hormone receptor interacts with transcription factors that cooperate in the transcription of a specific gene and prevents it. Glucocorticoids are able to prevent the transcription of the IL-2 gene and all other immune genes.

The ordinary glucocorticoids do not differentiate between transactivation and transrepression, therefore they influence the "wanted" genes and also "unwanted" ones. Currently, intensive research is focused on searching selective glucocorticoids. These will be able to transrepress the immune genes without affecting the metabolic and cardiovascular ones.

Immunosuppressive effect

Glucocorticoids diminish the cell immunity: they act by inhibiting genes that code the following cytokines: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-γ. Smaller production of cytokines causes reduced proliferation of T lymphocytes. This diminishes their effect and clone expansion of CD4+ cells (T-helper lymphocytes). Hereby, especially the IL-2 is important.

Glucocorticoids also diminish the humoral immunity. Like T lymphocytes, B lymphocytes express smaller amounts of IL-2 genes and of genes coding for IL-2 receptors. This means reduced B lymphocyte clone expansion and consequentially, the diminished synthesis of immunoglobulins.

Antiinflammatory action

Glucocorticoids influence all types of inflammatory reactions independently of their cause. They induct the synthesis of lipocortin-1 (annexin-1) that binds to phospholipid membranes and prevents the activity of phospholipase A2, as the enzyme is not able to come into contact with its substrate. Phospholipase A2 is involved in the first step of the production of some eicosanoids. The expression of genes coding for cyclooxygenase (COX-1 and COX-2), which catalyzes further steps, also diminishes.

Glucocorticoids also cause the release of lipocortin-1 in the extracellular space, where it binds to leukocyte mebrane receptors and inhibits epithelial adhesion, emmigration, chemotaxis, phagocytosis, respiratory burst, release of lysosome enzymes, release of chemotactic substances, release of the activator plasminogen and of other inflammatory mediators from neutrophils and macrophages. By the action of lypocortin-1 it is also possible to explain the inhibitory effect of glucocorticoids on the release of histamine from tissue basophils. Glucocorticoids successfully soothe all signs of inflammation, however they do not prevent infection. They also inhibit later reparative processes.

Glucocorticoid remedies

There are many different glucocorticoids in use: cortisol, dexamethasone, hydrocortisone, methylprednisolone (Medrol(R)), prednisone, prednisolone and others. They differ in pharmacokinetics (absorption factor, their half-life, the volume of distribution, clearance) and in pharmacodynamics (for example the capacity of mineralocorticoid activity: retention of sodium (Na+) and water; see also: renal physiology). They are primarily administered per os (by mouth), as they are well absorbed in the intestines, and topically on skin, but also by other ways. The majority (more than 90 per cent) of glucocorticoids bind different plasma proteins, however, they differ in their binding specifity. Endogenous glucocorticoids and some synthetic corticoids bind with high affinity the protein transcortin (also CBG, corticosteroid binding protein), while all of glucocorticoids are able to bind albumin. They are metabolised quickly in the liver, where they conjugate with a sulfate or glucuronic acid, and are secreted in urine.

Side effects of glucocorticoids

The side effects of glucocorticoids appear after a prolonged antiinflammatory and immunosuppressive therapy with high doses of glucocorticoids. All their metabolic effects are side effects (except for the substitutive therapy of the disfunction of hypophysis or the adrenal insufficiency):

  • The compromised immune response to infections and cancer cells.
  • Less effective response to injuries, because fibroblasts are inhibited. Fibroblasts synthesise collagen and glycosaminoglycans, that are involved in wound healing.
  • Iatrogenic Cushing's syndrome that develops after the prolonged application of glucocorticoids
  • Osteoporosis, because glucocorticoids inhibit the absorption of calcium (Ca2+) in the intestines and stimulate secretion of Ca2+ through kidneys. The lower quantity of Ca2+ in the blood activates osteoclasts and at the same time, the activity of osteoblasts is inhibited. This causes the loss of bone mass, therefore bones become fragile.
  • Adrenal insufficiency because of the negative feedback after the therapy is suddenly abolished, therefore it has to be abolished gradually.
  • Hyperglycemia.
  • Mineralocorticoid effects, if glucocorticoids are present in high amounts. This means retention of Na+ and water and secretion of potassium (K+).
  • The effect on neurons of the central nervous system.
  • Inhibition of growth in children, because glucocorticoids are proteolytic.
  • Muscle atrophy, of the same cause.

Therefore it is necessary that only minimal effective dose of glucocorticoids is used and the therapy is as short as possible.

Cytostatics

Main article: Cytostatics.

Cytostatics are drugs that inhibit the cell division and therefore damage or destroy cells. They are especially used in cancer therapy. However, because they are not only specific for cancer cells, they also affect all other quickly dividing cells. This can most often be observed as the chemotherapy side effects. It is nonetheless reasonable to use them, as the cancer cells divide faster than normal ones and are therefore more sensitive.

Cytostatics and the immune system

Quickly dividing cells are also T-lymphocytes and B-lymphocytes. As they recognise the specific antigen, they quickly proliferate to secure the adequate number of clones for the immune response. However, this makes them a suitable target of cytostatics. Therefore, we can use cytostatics whenever the immune response is not wanted. As immunosuppressants, cytostatics are used in smaller dosages as in the treatment of malign diseases. Their antiproliferative effect is in general not limited and it includes both T-lymphocytes and B-lymphocytes.

Classification of cytostatics and major representatives

On the basis of the site of action, cytostatics can be divided into four groups:

Mainly purine analogs are administered, as they are the most effective, while the others are less frequently used.

Alkylating agents

Their main representative are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds etc. They act cytostatically by affecting the DNA.

Cyclophosphamide is an alkylating agent and probably the most potent immunosuppressive substance. It inhibits the DNA replication by making covalent bonds with it. In small doses, it is very efficient in the treatment of systemic lupus erytematosus, autoimmune hemolytic anemias, Wegener's granulomatosis and other immune diseases. High doses of cyclophosphamide can cause pancytopenia and hemorrhagic cystitis.

Antimetabolites

Their main representatives are folic acid analogues (methotrexate), purine analogues (azathioprine, mercaptopurine), pyrimidine analogues, protein synthesis inhibitors. They affect all nucleic acids.

Methotrexate

Methotrexate is a folic acid analogue. It binds dihydrofolate reductase and prevents the synthesis of tetrahydrofolate. This way, it inhibits the synthesis of DNA, RNA and proteins (as tetrahydrofolate is involved in the synthesis of serine and methionine). It is used in the treatment of autoimmune diseases, as rheumatoid arthritis, and in some transplantations.

Azathioprine

Azathioprine is the main cytotoxic substance, used in immunosuppression. It is widely used in transplantations to control rejection reactions. It is nonezymathically cleaved to 6-mercaptopurine, which act as a purine analogue and the inhibitor of DNA synthesis. By preventing the clone expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and humoral immunity. It is also successful in the treatment of autoimmune diseases.

Cytotoxic antibiotics

Among these, dactinomycin is the most important. It is used in kidney transplantations. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mitramycin. All these substances act on DNA to mediate their effects.

Other cytostatics

Mitotic spindle inhibitors (vinca alkaloids, e.g. vincristine, vinblastine; podophyllins) are used in the therapy of some autoimmune diseases. They repress the M phase of the cell cycle. Vincristine depolimerizes mitotic spindle.

Antibodies

Antibodies are used in the induction therapy that by a quick and potent immunosuppression tries to prevent the acute rejection reaction.

Polyclonal antibodies

Heterologous polyclonal antibodies are obtained from the serum of different animals (e.g.rabbit, horse) that the pacient's thymocytes or lymphocytes have been injected to. The antilymphocyte (ALG) and antithymocyte antigens (ATG) are used. They are a part of the treatment of steroid-resistant acute rejection reaction and of the treatment of grave aplastic anemia. However, they are mostly used as additives to other immunosuppressives, which allows for the diminishment of the latter's dosage and their toxicity. The antibodies also allow the later 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 sickness anymore.

Polyclonal antibodies inhibit T lymphocytes and cause their lysis through the interaction with different cell surface markers (e.g. CD2, CD3, CD4, CD8, CD11a, CD18, CD45, CD3, CD4). The lysis is both complement mediated cytolysis and cell-mediated opsonization followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. This way, polyclonal antibodies inhibit cell-mediated immmune reactions, including the graft rejection, the delayed hypersensitivity (i.e. tuberculin skin reaction), and the graft-versus-host disease (GVHD), however their effect on the thymus-dependent antibody production is smaller. Currently (March 2005) there are two preparations available, Atgam (R), obtained from horse serum, and Thymoglobuline (R), obtained from rabbit serum.

Polyclonal antibodies act non-speciffically on all the lymphocytes and cause general immunosuppression that can lead to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially with cytomegalovirus. Therefore, the therapy must necessarily be performed in a hospital, where adequate isolation from infection is available.

As polyclonal antibodies are also highly immunogen, by almost all the patients an acute reaction develops in the first few days of the treatment. It is characterized by fever, sometimes rigor episodes and in some cases, even anaphylaxis develops. Later during the treatment, the serum sickness or by the immune complexes induced glomerulonephritis can develop. The serum sickness appears seven to fourteen days after the beginning of therapy. The patient suffers from fever, joint pain and erythema that can be soothed with the use of steroids and analgesics. Urticaria (hives) can also be present. Because of their immunogenicity, patients gradually develop a strong immune response against them, so these drugs cease to be effective. Their toxicity can be diminished by the use of highly purified serum fractions, intravenous application and their administration in the combination with other immunosuppressants, for example calcineurin inhibitors, cytostatics and cortisteroids. The most common combination is the simultaneous use of antibodies and cyclosporine.

Monoclonal antibodies

Monoclonal antibodies are much more specific, as they are directed towards exactly defined antigens and therefore, they cause fewer side effects. Especially important are antibodies against the IL-2 receptor (CD25) and against CD3, and probably new will appear. They are used to prevent rejection of transplanted organs, but also in the tracking of changes in lymphocyte subpopulations in immunosuppressive therapy.

Antibodies directed towards T-cell receptor

Till now, OKT3 is the only approved anti-CD3 antibody. It is a mous anti-CD3 monoclonal antibdy of the IgG2a type, that acts by binding the T-cell receptor complex, which is present on all differentiated T cells. In this way, it prevents T-cell activation and proliferation. It is one of the most potent immunosuppressive substances and is clinically used to control episodes of acute rejection, where steroids and/or polyclonal antibodies are not effective. As it is more specific than polyclonal antibodies, it is also used preventively in transplantations. The exact mechanism of OKT3 (R) is not adequatly explained yet. It is known that it binds the T-cell receptor complex of antigen (TCR/CD3). In the first few administrations, this binding causes non-specific activation of T cells, therefore a serious syndrome develops 30 to 60 minutes after its application. It is characterized by the fever, myalgia, headache, artralgia and can progress till the life-threatening reaction, that seriously affects cardiovascular system and the CNS and that a lengthy therapy is needed for. Later CD3 (R) blocks binding of TCR on antigen and causes change of conformation or the removal of the entire TCR3/CD3 from the T-cell surface. In this way, the CD3 antibodies lower the number of T cells, perhaps by sensitising them for the uptake by the reticular epithelial cells. The cross-binding of CD3 molecules also provokes an intracellular signal, which causes the anergy or the apoptosis of T cells, if they do not receive another signal by one of more costimulatory molecules. CD3 antibodies also cause the shift in the balance of T cells from Th1 cells to Th2 cells. When making a decision about the use of OKT3(R) in the treatment, it is necessary to consider not only its great effectiveness, bu also its toxic side effects. These are the risk of excessive immunosuppression and the risk that the patient develops neutralizing antibodies against it, which would mean that the drug would not be effective anymore. Although CD3(R) antibodies are more specific than polyclonal antibodies, they significantly lower the cell-mediated immunity and predispose patient to opportunistic infections and malignancies.

Antibodies directed towards IL-2 receptor

Interleukin-2 is an important immune system regulator that is necessary for the clone expansion and survival of activated lymphocytes T. Its effects are mediated by the trimer cell surface receptor IL-2a, composed of α, β and γ chains. IL-2a (CD25, T-cell activation antigen, TAC) is expressed only on those T lymphocytes, that were previously activated in the interaction with a foreign antigen or with IL-2 and is the only IL-2 specific molecule. Therefore, it has a special significance in the selective immunosuppressive treatment. On the basis of these findings, research focused on the development of effective and safe anti-IL-2 antibodies. The modification of mouse anti-Tac antibodies with the recombinant gene technology enabled the presentation of two himeric mouse/human anti-Tac antibodies in the year 1998. One of these is basiliximab (Simulect (R)) and the other is daclizumab (Zenapax (R)). They work by binding the α chain of the IL-2a receptor on the activated T lymphocytes. This prevents the IL-2 induced clonal expansion of activated lymphocytes and shortens their survival. These two remedies are used as a profilaxis of the acute organ rejection in the patients, who have both kidneys transplanted. They cause few side effects and are similarly effective, as both of them decrease the frequency of the acute rejection for approximately a third.

Drugs acting on immunophilins

Cyclosporine A

Together with tacrolimus, cyclosporin is a calcineurin inhibitor. It has been in use since 1984 and is one of the most widely used immunosuppressive drugs. It is a fungal peptide, composed of 11 amino acids.

When T-helper cell's receptor interacts with an antigen, the intracellular concentration of calcium in the cell rises. This increase activates the cytoplasmic phosphatase calcineurin. Calcineurin activates different transcription factors that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. This way, it directs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.

Cyclosporin is administered per os or intravenously. It reaches its highest concentration three to four hours later. Its tissue concentrations are to four times higher than in the plasma. In the tissue, it binds to the cytosolic immunophilin, named cyclofilin. The complex then binds to calcineurin and inhibits it. Cyclosporin is metabolized in the liver and secreted to the bile; its half time is about 24 hours.

Cyclosporin is used in the treatment of acute rejection reactions, however because of its nephrotoxicity, it is substituted with newer immunosuppressants more and more. The nephrotoxicity affects 40 — 70% of patients. Especially the proximal tubules are destroyed. Other less frequent side effects are hypertension, venous thrombosis, tremor, headache, parestesias and hyperkalemia.

Tacrolimus (Prograf(TM), FK506)

Tacrolimus is a fungal product (Streptomyces tsukubaensis). It is a macrolide lactone and acts by inhibiting calcineurin.

Tacrolimus is used particularly in the transplantation of kidney and liver. It can be administered per os or intravenously, and 99% of it degrades in the liver. Its half-life is approximately 12 hours. Tacrolimus binds an immunophilin, after which the complex binds to calcineurin and inhibits its phosphatase activity. In this way, it prevents the first phase of the T lymphocyte activation (passage of G0 into G1 phase).

Tacrolimus is more potent than cyclosporine and has less pronounced side effects. Among these, the most frequent are nephropathies, convulsions, tremor, hypertension, diabetes, hyperkalemia, insomnia, neuropathies and gout.

Sirolimus (Rapamune (Tm), Rapamicin)

Actinomycetes Streptomyces hygroscopicus produce it. Chemically it is a macrolide lactone.

Sirolimus is used as an immunosuppresant in the transplantation. Although it is a structural analogue of tacrolimus, it acts somewhat differently and has different side effects. It is administered solely per os in the form of tablets or a solution. It is metabolized in the liver by the CYP34A4 cytochrome, with the half time of about 62 hours. It is excreted particularly in feces, only 2% in urine.

Contrary to cyclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, it 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 a special protein. Therefore, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. Indirectly it inhibits several kinases and phosphatases of T lymphocytes and prevents the transmission of signal into their activity and the continuation of the cell cycle from G1 phase to S phase. Similarly, it prevents B cell differentiation in the plasma cells, which means a lower quantity of IgM, IgG and IgA antibodies is produced. It acts immunoregulatory.

Sirolimus' side effects are hyperlipidemia, leuko- and thrombocytopenia, anemia and hypokalemia. Its toxicity to the transplanted organ has not been proved, therefore it substitutes cyclosporin in kidney transplantations.

Other remedies

Interferons

Main article:Interferons.

Interferons (IFNs) are cell proteins of the cytokine class and important antiviral factors, but they are synthesized also in response to other stimuli. Three major groups of interferons are known: IFN-α (leukocytic), IFN-β (fibroblastic) and IFN-γ (immune). These differ in their physical, chemical and biological properties.

In a majority of cases, the production of interferons is induced by other cytokines, e.g. IL-1, IL-2, TNF and CSF. IFN-α and IFN-β are synthesized in many cell types - macrophages, fibroblasts, endothelial cells, osteoblasts and others. Their synthesis is mainly caused by the appearance of viruses in the body. IFN-γ is produced in antigen activated cells T in inflammatory and autoimmune conditions and has a central role in the immune response control.

The effect of interferons

All interferons have antiviral and antitumour effect and they cause fever. Beside this, IFN-β and IFN-γ have anti-inflammatory and immunosuppressive effects:

  • IFN-γ is an inflammatory cytokine that by as yet unknown mechanism triggers apoptosis in lymphocytes
  • IFN-β inhibits the progression of multiple sclerosis. By an as yet unknown mechanism, it inhibits the production of Th1 cytokines and the monocyte activation.

The production of IFN-γ during the infection is highly important to destroy foreign antigens and overcome the disease, however at the same time it can lead to autoimmune activity. Namely, IFN-γ has an exceptionally important immunoregulatory function.

When used in the systemic therapy, IFN-α and IFN-γ are mostly administered by an intramuscular injection. Interferons hardly traverse the placenta and the blood-brain barrier. Their metabolism and excretion take place mainly in the liver and kidneys.

The injection of interferons in the muscle, vein or under skin is generally well tolerated. The most frequent side effects are flu-like symptoms: raised body temperature, feeling ill, fatigue, headache, muscle pain, and convulsion. Erythema, pain and hardness on the spot of injection are also frequently observed. Rarely, patients experience their hair falling out, dizziness and depression. All known effects are reversible and disappear a few days after the therapy is finished.

Opioids

A prolonged taking of opioids (analgesics, illegal drugs) can cause immunosuppression, which means the risk of infection is increased. Their effects are not yet fully researched, however they cause diminished migration of leukocytes.

TNF-α binding drugs

TNF-α binding drugs are proteins or antibodies, that bind to TNF (tumor necrotising factor) and prevent its action, that is the production of IL-1 and IL-6 and the adhesion of molecules that activate lymphocytes. They are intravenously administered and are used in the treatment or inhibition of progression of rheumatoid arthritis, ankylosing spondylitis, Chron's disease etc. Besides respiratory and other infections, their side effects also include the edema on the spot of administration, pancytopenia and sometimes vasculitis develops. In prolonged therapy, the risk of lymphoma is increased. The representatives of this class of drugs are Etanercept (Enbrel (Tm)) and Infliximab (Remicade(TM)).

Mycophenolic acid

Mycophenolic acid (MPA) is an active component produced from Mycophenolate mofetil (MMF) and a new substance Mycophenolate sodium (Myfortic(R)). It acts as a non-competitive, selective and reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH), which is a key enzyme in de novo gvanosin nucleotide synthesis. In contrast to other human body cells, lymphocytes B and T are much more dependent of the de novo synthesized gvanosin.

Small biological agents

FTY120

FTY120 is a new synthetic immunosuppressor, a chemical modification of the ISP-1 metabolite of the fungus Iscaria sincaliri. It is a structural analogue of sphyngosine and gets phosphorylated with the sphyngosine kinase in the cell. It increases the expression or changes the function of certain adhesion molecules (α4/β7 integrine) 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.

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