Immunomodulatory drugs and immunosuppressants also have another name - immunosuppressants. They are used to slow down the functioning and proliferation of immune system cells. They need to be taken when it is necessary to stop immune reactions, for example, during organ transplants, autoimmune pathologies, the musculoskeletal system and other serious diseases.
Features of immunosuppressants
Immunosuppressive drugs should be used when other treatment methods have been tried and the desired results have not been achieved, and the chances of a positive outcome are much higher than the risks of their use. Almost all of the list of immunosuppressive drugs have immunosuppressive activity and have a broad effect. Their use reduces antibacterial and antitumor immunity, increases the risk of infectious diseases and oncological pathologies.
Since diseases and health complications in many cases have an unfavorable outcome, contraindications for treatment with immunosuppressants are insignificant.
Scientists are working to give the drug a narrow scope of action, that is, so that it acts on one specific problem without affecting other cells.
Inhibition of immune responses[edit | edit code]
Source:
Visual Pharmacology
.
Author
: X. Lulman.
Per. with him. Ed.
: M.: Mir, 2008
Inhibition of immune responses is useful in organ transplantation to prevent transplant rejection and in autoimmune diseases. Immunosuppression, in turn, implies a weakening of protection against infections, as well as the risk of malignant neoplasms.
A. Immune reactions and their inhibition
A specific immune reaction begins with the attachment of an antigen to a lymphocyte. B lymphocytes “recognize” the surface structure using membrane receptors, which are similar to the antibodies that are then formed. T-lymphocytes recognize antigens presented on the surface of macrophages with the help of molecules of the major histocompatibility complex (MHC, from English, major histocompatibility complex). T cells have CD3 and CD4 (T helper) or CD8 (cytotoxic T lymphocyte) molecules on their surface that interact with MHC. In addition to antigen recognition, lymphocyte activation requires stimulation with mediators such as cytokines. Interleukin 1 is produced by macrophages, other interleukins, including Intelukin 2, by T helper cells. Antigen-specific lymphocytes proliferate and an immune response occurs.
I. Impact on the antigen recognition mechanism
. Muromonab-SRZ is a mouse monoclonal antibody against CD3, which is involved in antigen recognition and interacts with T lymphocytes (used in transplant rejection) in the treatment of multiple sclerosis. This disease is attributed to autoaggression caused by the action of T lymphocytes against oligodendrocytes, which form the myelin sheath of neurons in the central nervous system. Myelin protein apparently acts as an antigen. Glatiramer is similar to it; it inhibits antigen receptors, which enhances antigen recognition by lymphocytes.
II. Inhibition of cytokine production and activity
. Glucocorticoids modulate the expression of many genes. For example, they block the formation of interleukins 1 and 2, which in turn inhibits the immune response of T helper cells. Glucocorticoids interact with other cytokines and inflammatory mediators. They are prescribed for transplant rejection, autoimmune diseases and allergic reactions. Systemic use is dangerous due to the development of Cushing's syndrome.
Cyclosporine A
and related drugs inhibit the formation of cytokines, including interleukin 2. However, unlike glucocorticoids, cyclosporine A is not involved in all metabolic processes.
Anakinra
- a genetically engineered drug, an antagonist of interleukin 1 receptors. Anakinra is used in the treatment of rheumatoid arthritis (p. 340).
Daclizumab
and
basiliximab
are monoclonal antibodies against the interleukin 2 receptor. They consist of mouse PaB fragments and a human Fc fragment. Used in cases of transplant rejection.
Glatiramer acetate
consists of synthetic peptides with different chain lengths, composed of amino acids in a random sequence: glutamic acid, lysine, alanine and tyrosine (the name glatiramer comes from the first letters of the amino acids - they are highlighted). This drug can be used along with p-interferon
III. Disruption of cell metabolism by inhibition of proliferation
. Some cytostatics are also used as immunosuppressants, but in lower doses than for the treatment of tumors. These include azatoprine, methotrexate and cyclophosphamide. They have a nonspecific antiproliferative effect on both B and T cells. Mycophenolate mofetil acts specifically on the proliferation of lymphocytes and blocks inosine monophosphate dehydrogenase, which is necessary for lymphocytes to synthesize purines. The drug is used for acute transplant rejection reactions.
IV. Immune serum against T cells is obtained by immunizing laboratory animals with human T lymphocytes. The drug damages T-lymphocytes and is used to weaken the transplant rejection reaction.
Kinds
Taking into account the effect of the drug on human immunity, they are classified into several groups:
- Completely suppress the immune system;
- Selective influence;
- To alleviate the manifestations of autoimmune diseases;
- Anti-inflammatory effect – necessary for disorders of brain function.
There is another classification of drugs:
- Antitumor drugs;
- Anti-inflammatory medications;
- Gold preparations.
There are also several generations of these funds:
- "Azathioprine", "Methotrexate".
- Glucocorticoids.
- "Cyclosporine."
- Daclizumab.
Classification of immunosuppressants
Immunosuppressant drugs are classified into:
- cytostatics: antimetabolites: azathioprine, methotrexate, mycophenolic acid, sodium mycophenolate;
- alkylating agents: cyclophosphamide;
An immunosuppressive effect is also inherent in antimalarial drugs - chloroquine, hydroxychloroquine, gold drugs - auranofin, sodium aurothiomalate, aurothioglucose.
Operating principle
Immunospressors have a specific mechanism of operation:
- "Azathioprine" and "Methotrexate" prevent cell division and stop the formation of protein elements. The result occurs slowly and will be noticeable only after half a year from the moment of use. These drugs have an antitumor effect. Also, if you take it in small quantities, an anti-inflammatory result will be achieved. The first drug contains fewer toxic substances.
- "Cyclosporine." A selective and reversible effect on the cellular immune response is achieved. The duration of functioning of allogeneic transplants of various organs increases.
- Glucocorticoids. They have a strong immunosuppressive effect. They stop the work of macrophages and lymphocytes, preventing them from entering the blood. If taken in large quantities, the work of immunoglobulin will be suspended. They have a pronounced and rapid anti-inflammatory effect.
- Gold preparations, collecting in infected joint tissues, reduce the phagocytic work of macrophages, reduce the content of immunoglobulin in plasma, which leads to a decrease in its destructive effect on the joints. The result will be noticeable after 6 months.
- Daclizumab. This is a very strong drug, which achieves a more powerful cytostatic effect.
Immunosuppressive drug
Immunosuppressants, also known as immunosuppressants, immunosuppressants, and anti-rejection drugs, are medications that suppress or prevent the activity of the immune system.
Classification
Immunosuppressants can be divided into five groups:
- glucocorticoids
- cytostatics
- antibodies
- drugs acting on immunophilins
- other drugs
Glucocorticoids
In pharmacological (supraphysiological) doses, glucocorticoids such as prednisone, dexamethasone and hydrocortisone are used to suppress a variety of allergic, inflammatory and autoimmune diseases. They are also administered as post-transplant immunosuppressants to prevent acute graft rejection and graft-versus-host disease. However, they do not prevent infection and also inhibit subsequent repair processes.
Immunosuppressive mechanism
Glucocorticoids suppress cellular immunity. They act by inhibiting genes that encode the cytokines Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and TNF-alpha, the most important of them. including IL-2. Less cytokine production reduces T cell proliferation.
Glucocorticoids also suppress humoral immunity by causing B cells to express fewer IL-2 and IL-2 receptors. This reduces both the expansion of B cell clones and the synthesis of antibodies.
Anti-inflammatory effects
Glucocorticoids affect all types of inflammatory phenomena, regardless of their cause. They induce the synthesis of lipocortin-1 (annexin-1), which then binds to cell membranes, preventing phospholipase A2 from contacting its substrate arachidonic acid. This results in decreased production of eicosanoids. Cyclooxygenase (COX-1 and COX-2) expression is also suppressed, enhancing the effect.
Glucocorticoids also stimulate the release of lipocortin-1 into the extracellular space, where it binds to receptors on leukocyte membranes and suppresses various inflammatory processes: 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 mast cells.
Cytostatics
Cytostatics inhibit cell division. In immunotherapy they are used in lower doses than in the treatment of malignant diseases. They influence the proliferation of both T cells and B cells. Purine analogues are most often used due to their maximum effectiveness.
Alkylating agents
The alkylating agents used in immunotherapy are nitrogen mustard (cyclophosphamide), nitrosoureas, platinum compounds and others. Cyclophosphamide (Baxter's Cytoxan) is probably the most potent immunosuppressive compound. In small doses, it is very effective in the treatment of systemic lupus erythematosus, autoimmune hemolytic anemias, granulomatosis with polyangiitis and other immune diseases. High doses cause pancytopenia and hemorrhagic cystitis.
Antimetabolites
Antimetabolites disrupt the synthesis of nucleic acids. These include:
- folic acid analogues, such as methotrexate
- purine analogs such as azathioprine and mercaptopurine
- pyrimidine analogs such as fluorouracil
- protein synthesis inhibitors.
Methotrexate
Methotrexate is an analogue of folic acid. It binds dihydrofolate reductase and prevents the synthesis of tetrahydrofolate. It is used in the treatment of autoimmune diseases (such as rheumatoid arthritis or Behçet's disease) and in transplantation.
Azathioprine and mercaptopurine
Azathioprine (Imuran Promethea) is a major immunosuppressive cytotoxic substance. It is widely used to control graft rejection reactions. It is cleaved non-enzymatically to mercaptopurine, which acts as a purine analog and inhibitor of DNA synthesis. Mercaptopurine itself can also be administered directly.
By preventing clonal expansion of lymphocytes during the induction phase of the immune response, it affects both cellular and humoral immunity. It is also effective in treating autoimmune diseases.
Cytotoxic antibiotics
Among them, dactinomycin is the most important. Used in kidney transplantation. Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin.
Antibodies
Antibodies are sometimes used as a rapid and potent immunosuppressive therapy to prevent acute rejection reactions, as well as for targeted treatment of lymphoproliferative or autoimmune diseases (eg, anti-CD20 monoclonal drugs).
Polyclonal antibodies
Heterologous polyclonal antibodies are obtained from the blood serum of animals (for example, rabbit, horse) and injected with the patient's thymocytes or lymphocytes. Antilymphocyte (ALG) and antithymocyte antigens (ATG) are used. They are part of the steroid-resistant acute rejection response and treatment of severe aplastic anemia. However, they are added mainly to other immunosuppressants to reduce their dosage and toxicity. They also allow switching to cyclosporine therapy.
Polyclonal antibodies inhibit T lymphocytes and cause their lysis, which is both complement-mediated cytolysis and cell-mediated opsonization, followed by removal of reticuloendothelial cells from the circulation in the spleen and liver. Thus, polyclonal antibodies suppress cell-mediated immune reactions, including graft rejection, delayed hypersensitivity (i.e., tuberculin skin reaction), and graft-versus-host disease (GVHD), but affect thymus-dependent antibody production.
As of March 2005, two drugs are available on the market: atgam, derived from horse serum, and thymoglobulin, derived from rabbit serum. Polyclonal antibodies affect all lymphocytes and cause general immunosuppression, which can lead to post-transplant lymphoproliferative disorders (PTLD) or serious infections, especially with cytomegalovirus. To reduce these risks, treatment is carried out in a hospital where there is adequate isolation from infection. They are usually administered intravenously over five days in appropriate amounts. Patients remain in the hospital for up to three weeks to give the immune system time to recover to the point where there is no longer a risk of serum sickness.
Due to the high immunogenicity of polyclonal antibodies, almost all patients experience an acute response to treatment. It is characterized by fever, bouts of rigor, and even anaphylaxis. Later during treatment, some patients develop serum sickness or immune complex glomerulonephritis. Serum sickness occurs seven to fourteen days after the start of therapy. The patient suffers from fever, joint pain and erythema, which can be relieved with steroids and analgesics. Urticaria (urticaria) may also be present. Their toxicity can be reduced by using highly purified serum fractions and intravenous administration in combination with other immunosuppressants, such as calcineurin inhibitors, cytotoxic drugs and corticosteroids. The most common combination is the simultaneous use of antibodies and cyclosporine to prevent patients from gradually developing a strong immune response to these drugs, reducing or eliminating their effectiveness.
Monoclonal antibodies
Monoclonal antibodies are directed against precisely defined antigens. Therefore, they cause fewer side effects. Particularly important are the IL-2 receptor (CD25-) and CD3-directed antibodies. They are used to prevent organ transplant rejection and also to monitor changes in lymphocyte subpopulations. It is reasonable to expect similar new drugs to become available in the future.
Antibodies targeting T cell receptors
Muromonab-CD3 is a murine anti-CD3 monoclonal antibody of the IgG2a type that has previously been used to prevent T cell activation and proliferation by binding to the T cell receptor complex present on all differentiated T cells. Thus, it was one of the first potent immunosuppressants and was administered to control episodes of acute rejection resistant to steroids and/or polyclonal antibodies. Because it acts more specifically than polyclonal antibodies, it has also been used prophylactically in transplantation. However, muromonab-CD3 is no longer produced, and this murine monoclonal antibody has been replaced in the clinic by chimeric, humanized, or human monoclonal antibodies.
The mechanism of action of muromonab is only partially understood. The molecule is known to bind the TCR/CD3 receptor complex. During the first few administrations, this binding nonspecifically activates T cells, resulting in a severe syndrome within 30 to 60 minutes. It is characterized by fever, myalgia, headache and arthralgia. Sometimes develops with a life-threatening reaction of the cardiovascular system and central nervous system, requiring long-term treatment. After this period, CD3 blocks TCR-antigen binding and causes a conformational change or removal of the entire TCR3/CD3 complex from the surface of T cells. This reduces the number of available T cells, possibly by sensitizing them for uptake by epithelial reticular cells. Cross-linking of CD3 molecules also activates an intracellular signal causing T cell anergy or apoptosis unless the cells receive another signal through a costimulatory molecule. CD3 antibodies shift the balance from Th1 cells to Th2 cells because CD3 stimulates Th1 activation.
The patient may develop neutralizing antibodies that reduce the effectiveness of muromonab-CD3. Muromonab-CD3 may cause excessive immunosuppression. Although anti-CD3 antibodies are more specific than polyclonal antibodies, they significantly reduce cellular immunity, predisposing the patient to opportunistic infections and malignancies.
Antibodies directed against the IL-2 receptor
Interleukin-2 is an important regulator of the immune system, essential for clonal propagation and survival of activated T lymphocytes. Its effects are mediated by the trimeric cell surface receptor IL-2a, consisting of α, β and γ chains. IL-2a (CD25, T cell activation antigen, TAC) is expressed only by already activated T lymphocytes. Therefore, it is of particular importance for selective immunosuppressive treatment, and research has focused on the development of effective and safe antibodies against IL-2. Using recombinant gene technology, mouse anti-Tac antibodies were modified, leading to the presentation of two chimeric mouse/human anti-Tac antibodies in 1998: basiliximab (Simulect) idaclizumab (Zenapax). These drugs act by binding to the α chain of the IL-2a receptor, preventing IL-2-induced clonal proliferation of activated lymphocytes and reducing their survival. They are used to prevent acute organ rejection after bilateral kidney transplantation, both are equally effective and have few side effects.
Drugs acting on immunophilins
Cyclosporine
Like tacrolimus, cyclosporine (Sandimmune from Novartis) is a calcineurin inhibitor (CNI). It has been used since 1983 and is one of the most widely used immunosuppressants. This is a cyclic mushroom peptide consisting of 11 amino acids.
Cyclosporine is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T lymphocytes. This complex of cyclosporine and cyclophilin inhibits the phosphatase calcineurin, which under normal conditions induces the transcription of interleukin-2. The drug also inhibits the production of lymphokines and the release of interleukin, which leads to decreased function of effector T cells.
Cyclosporine is used in the treatment of acute rejection reactions, but has largely been replaced by new, and less nephrotoxic, immunosuppressants.
Calcineurin inhibitors and azathioprine have been associated with post-transplant malignancies and skin cancer in transplant recipients. Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can lead to significant morbidity and mortality. Several studies indicate that calcineurin inhibitors have oncogenic properties, mainly related to the production of cytokines that promote tumor growth, metastasis, and angiogenesis.
This drug has been reported to reduce the frequency of T regulatory cells (T-Reg), and after switching from CNI monotherapy to mycophenolate monotherapy, patients were found to have increased graft success and T-Reg frequency.
Tacrolimus
Tacrolimus (trade names Prograf, Astagraf XL, Envarsus XR) is a product of the bacterium Streptomyces tsukubaensis. It is a macrolide lactone that inhibits calcineurin.
The drug is used primarily in liver and kidney transplants, although some clinics use it in heart, lung, and heart/lung transplants. It binds to the immunophilin FKBP1A, followed by binding of the complex to calcineurin and inhibition of its phosphatase activity. Thus, it prevents the cell from transitioning from the G 0 phase to the G 1 phase of the cell cycle. Tacrolimus is more effective than cyclosporine and has fewer side effects.
Sirolimus
Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone produced by the actinomycete bacterium Streptomyces hygroscopicus. It is used to prevent rejection reactions. Although it is structurally similar to tacrolimus, it works slightly differently and has different side effects.
Unlike cyclosporine and tacrolimus, drugs that affect the first phase of T-lymphocyte activation, sirolimus affects the second phase, namely signal transduction and clonal proliferation of lymphocytes. It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but rather inhibits another protein, mTOR. Consequently, sirolimus acts synergistically with cyclosporine and, in combination with other immunosuppressants, has few side effects. In addition, it indirectly inhibits several T-lymphocyte-specific kinases and phosphatases, thereby preventing their transition from G 1 to S phase of the cell cycle. Similarly, sirolimus prevents B cells from differentiating into plasma cells by reducing the production of IgM, IgG, and IgA antibodies.
It is also active against PI3K/AKT/mTOR-dependent tumors.
Everolimus
Everolimus is an analogue of sirolimus and also an mTOR inhibitor.
Zotarolimus
Zotarolimus is a semisynthetic derivative of sirolimus that is used in drug-eluting stents.
Other drugs
Interferons
IFN-β suppresses Th1 cytokine production and monocyte activation. It is used to slow the progression of multiple sclerosis. IFN-γ can trigger lymphocyte apoptosis.
Opioids
Long-term opioid use can cause immunosuppression of both innate and adaptive immunity. A decrease in proliferation as well as immune function is observed in both macrophages and lymphocytes. These effects are thought to be 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 circulating receptor such as infliximab (Remicade), etanercept (Enbrel), or adalimumab (Humira) that binds to TNF-alpha, preventing it from inducing IL synthesis -1 and IL-6 and adhesion of lymphocyte-activating molecules. They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease and psoriasis.
These drugs may increase the risk of contracting tuberculosis or cause an underlying infection to become active. Infliximab and adalimumab have warning statements on their labels stating that patients should be screened for latent TB infection and treatment should be initiated before starting therapy with them.
TNF or the effects of TNF are also inhibited by various natural compounds, including curcumin (an ingredient in turmeric) and catechins (in green tea).
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 synthesis of guanosine nucleotides. Unlike other human cell types, B and T lymphocytes are highly dependent on this process. Mycophenolate mofetil is used in combination with cyclosporine or tacrolimus in transplant patients.
Small biological agents
Fingolimod is a new synthetic immunosuppressant drug that is currently undergoing phase 3 clinical trials. It increases the expression or alters the function of certain adhesion molecules (α4/β7 integrin) in lymphocytes so that they accumulate in lymphatic tissue (lymph nodes) and their number in the bloodstream decreases. In this respect, it differs from all other known immunosuppressants.
Myriocin has been reported to be 10 to 100 times more effective than cyclosporine.
Therapy
Immunosuppressive drugs are used in immunosuppressive therapy for:
- Prevention of failure of transplanted organs and tissues (eg, bone marrow, heart, kidney, liver)
- Treat autoimmune diseases or diseases that are most likely of autoimmune origin (eg, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, psoriasis, vitiligo, granulomatosis with polyvasculitis, systemic lupus erythematosus, systemic sclerosis/scleroderma, sarcoidosis, focal segmental glomerulosclerosis, Crohn's disease, Behçet's disease , pemphigus, ankylosing spondylitis and ulcerative colitis).
- Treatment of certain other non-autoimmune inflammatory diseases (eg, long-term control of allergic asthma).
Clinical and pharmacological principles
To achieve the desired result from the use of drugs, you need to take into account some clinical and pharmacological principles:
- Large doses - small doses;
- Small anti-inflammatory effect – large anti-inflammatory effect;
- Rapid treatment - long-term treatment;
- Different time to achieve results - the effect will be noticeable after a specific period of time (day, week, month, six months);
- Suppression of DNA production - suppression of RNA separation.
Features of application
Precautions must be taken when taking these medications. Firstly, they should be taken with caution during pregnancy, breastfeeding, kidney and liver problems, infectious infections, and impaired bone marrow function. They are prescribed for the following diseases and surgical interventions:
- liver disease;
- psoriasis;
- organ and tissue transplantation;
- autoimmune diseases;
- multiple sclerosis;
- myocardium in chronic form.
Agents with selective effects do not interfere with the appearance of protective cells in infectious diseases and have virtually no effect on antitumor immunity.
Features of treatment with immunosuppressive drugs
Immunosuppressant drugs have a large number of side effects, in addition, they significantly affect the action of other drugs, increasing their toxicity. Therefore, immunosuppressants are used only as directed and under the strict supervision of a doctor.
Immunosuppressant drugs, by suppressing the body's immune defense, make it much more sensitive to infectious diseases - bacterial, viral, fungal. Immunosuppressants also mask the symptoms of acute infectious diseases, including colds, which can lead to the development of more severe conditions, such as pneumonia.
