Chelyabinsk State University
On the topic: "Cytokines"
Completed by: Ustyuzhanina D.V.
Group BB 202-1
Chelyabinsk
General characteristics of cytokines
The mechanism of action of cytokines
Violation mechanism
Interleukins
Interferons
TNF: Tumor necrosis factor
colony stimulating factors
1. Cytokines
Cytokines are specific proteins with the help of which various cells of the immune system can exchange information with each other and coordinate actions. The set and amounts of cytokines acting on cell surface receptors - the "cytokine environment" - represent a matrix of interacting and frequently changing signals. These signals are complex due to the wide variety of cytokine receptors and because each of the cytokines can activate or inhibit several processes, including its own synthesis and the synthesis of other cytokines, as well as the formation and appearance of cytokine receptors on the cell surface. Different tissues have their own healthy "cytokine environment". More than a hundred different cytokines have been found.
Cytokines differ from hormones in that they are produced not by endocrine glands, but by various cell types; In addition, they control a much wider range of target cells than hormones.
Cytokines include some growth factors such asinterferons, tumor necrosis factor (TNF) , rowinterleukins, colony stimulating factor (CSF) and many others.
Cytokines include interferons, colony-stimulating factors (CSF), chemokines, transforming growth factors; tumor necrosis factor; interleukins with established historical serial numbers and some other endogenous mediators. Interleukins with serial numbers starting from 1 do not belong to one subgroup of cytokines associated with a common function. They, in turn, can be divided into pro-inflammatory cytokines, growth and differentiation factors of lymphocytes, and individual regulatory cytokines.
Structure classification:
Functional classification:
Classification of cytokine receptors
Structural and functional classification of cytokines
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Families of cytokines |
Subgroups and ligands |
Basic biological functions |
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InterferonsItype |
IFN , , , , , , IL-28, IL-29 (IFN ) |
Antiviral activity, antiproliferative, immunomodulatory action |
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Hematopoietic cell growth factors |
stem cell factor (kit- ligand, steel factor), flt-3 ligand, G-CSF, M-CSF, IL-7, IL-11 |
Stimulation of proliferation and differentiation of various types of progenitor cells in the bone marrow, activation of hematopoiesis |
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Ligandsgp140: IL-3, IL-5, GM-CSF |
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Erythropoietin, Thrombopoietin |
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Interleukin-1 superfamily and FRF |
FRF family: Acidic FGF, basic FGF, FRF3 - FRF23 |
Activation of proliferation of fibroblasts and epithelial cells |
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IL-1 family (F1-11): IL-1α, IL-1β, IL-1 receptor antagonist, IL-18, IL-33, etc. |
Pro-inflammatory action, activation of specific immunity |
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Tumor necrosis factor family |
TNF, lymphotoxins α and β,Fas-ligand, etc. |
Pro-inflammatory effect, regulation of apoptosis and intercellular interaction of immunocompetent cells |
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Interleukin-6 family |
Ligandsgp130: IL-6, IL-11, IL-31, Oncostatin-M, Cardiotropin-1,Leukemia inhibitory factor, Ciliary neurotrophic factor |
Pro-inflammatory and immunoregulatory action |
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Chemokines |
SS, SHS (IL-8), SH3S, S |
Regulation of chemotaxis of various types of leukocytes |
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Interleukin-10 family |
IL-10,19,20,22,24,26 |
Immunosuppressive action |
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Cinterleukin-12 family |
IL-12,23,27 |
Regulation of differentiation of T-lymphocytes of helpers |
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Cytokines of T-helper clones and regulatory functions of lymphocytes |
T-helpers type 1: IL-2, IL-15, IL-21, IFN |
Activation of cellular immunity |
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T-helpers 2 types: IL-4, IL-5, IL-10, IL-13 |
Activation of humoral immunity, immunomodulating effect |
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Ligands of the γ-chain of the IL-2 receptor: IL-4 IL-13 IL-7 TSLP |
Stimulation of differentiation, proliferation and functional properties of various types of lymphocytes, DC, NK cells, macrophages, etc. |
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Interleukin 17 family |
IL-17 A, B, C, D, E, F |
Activation of the synthesis of pro-inflammatory cytokines |
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Superfamily of nerve growth factor, platelet growth factor and transforming growth factors |
Nerve growth factor family: NGF, brain-derived neurotrophic factor |
Regulation of inflammation, angiogenesis, neuronal function, embryonic development and tissue regeneration |
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Growth factors from platelets (PDGF), angiogenic growth factors (VEGF) |
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TRF family: TRF , activins,inhibins,nodal, Bonemorphogenicproteins, Mullerianinhibitorysubstance |
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Epidermal growth factor family |
ERF, TRFα, etc. | ||
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Family of insulin-like growth factors |
IRF-I, IRF-II |
Stimulation of proliferation of various cell types |
General properties of cytokines:
1. Cytokines are polypeptides or proteins, often glycosylated, most of them have MM from 5 to 50 kDa. Biologically active cytokine molecules can consist of one, two, three or more of the same or different subunits. 2. Cytokines do not have antigenic specificity of biological action. They affect the functional activity of cells involved in the reactions of innate and acquired immunity. Nevertheless, by acting on T- and B-lymphocytes, cytokines are able to stimulate antigen-induced processes in the immune system. 3. For cytokine genes, there are three variants of expression: a) stage-specific expression at certain stages of embryonic development, b) constitutive expression for the regulation of a number of normal physiological functions, c) inducible type of expression, characteristic of most cytokines. Indeed, most cytokines outside of the inflammatory response and immune response are not synthesized by cells. The expression of cytokine genes begins in response to the penetration of pathogens into the body, antigenic irritation or tissue damage. Pathogen-associated molecular structures serve as one of the strongest inducers of the synthesis of pro-inflammatory cytokines. To start the synthesis of T-cell cytokines, activation of cells with a specific antigen with the participation of the T-cell antigen receptor is required. 4. Cytokines are synthesized in response to stimulation for a short period of time. Synthesis is terminated by a variety of autoregulatory mechanisms, including increased RNA instability, and by the existence of negative feedbacks mediated by prostaglandins, corticosteroid hormones, and other factors. 5. The same cytokine can be produced by different histogenetic origin cell types of the body in different organs. 6. Cytokines can be associated with the membranes of the cells synthesizing them, having a full spectrum of biological activity in the form of a membrane form and manifesting their biological effect during intercellular contact. 7. The biological effects of cytokines are mediated through specific cellular receptor complexes that bind cytokines with very high affinity, and individual cytokines can use common receptor subunits. Cytokine receptors can exist in a soluble form, retaining the ability to bind ligands. 8. Cytokines have a pleiotropic biological effect. The same cytokine can act on many types of cells, causing different effects depending on the type of target cells. The pleiotropic effect of cytokines is provided by the expression of cytokine receptors on cell types of different origins and functions and by signal transduction using several different intracellular messengers and transcription factors. 9. Interchangeability of biological action is characteristic of cytokines. Several different cytokines can cause the same biological effect or have similar activity. Cytokines induce or suppress the synthesis of themselves, other cytokines and their receptors. 10. In response to an activation signal, cells simultaneously synthesize several cytokines involved in the formation of a cytokine network. Biological effects in tissues and at the level of the body depend on the presence and concentration of other cytokines with synergistic, additive or opposite effects. 11. Cytokines can influence the proliferation, differentiation and functional activity of target cells. 12. Cytokines act on cells in various ways: autocrine - on the cell that synthesizes and secretes this cytokine; paracrine - on cells located near the producer cell, for example, in the focus of inflammation or in the lymphoid organ; endocrine - remotely on the cells of any organs and tissues after entering the circulation. In the latter case, the action of cytokines resembles the action of hormones.
One and the same cytokine can be produced by different histogenetic origin cell types of the body in different organs and act on many cell types, causing different effects depending on the type of target cells.
Three variants of the manifestation of the biological action of cytokines.
Apparently, the formation of the cytokine regulation system evolved along with the development of multicellular organisms and was due to the need to form mediators of intercellular interaction, which may include hormones, neuropeptides, adhesion molecules, and some others. In this regard, cytokines are the most universal regulatory system, since they are able to exhibit biological activity both remotely after secretion by the producer cell (locally and systemically) and during intercellular contact, being biologically active in the form of a membrane form. This system of cytokines differs from adhesion molecules, which perform narrower functions only with direct cell contact. At the same time, the cytokine system differs from hormones, which are mainly synthesized by specialized organs and act after entering the circulation system. The role of cytokines in the regulation of the physiological functions of the body can be divided into 4 main components: 1. Regulation of embryogenesis, laying and development of organs, incl. organs of the immune system.2. Regulation of certain normal physiological functions.3. Regulation of protective reactions of the body at the local and systemic levels.4. Regulation of tissue regeneration processes.
Cytokines are about 100 complex proteins involved in many immune and inflammatory processes in the human body. They do not accumulate in the cells that produce them and are quickly synthesized and secreted.
Properly functioning cytokines keep the immune system running smoothly and efficiently. Their characteristic feature is the versatility of action. In most cases, they exhibit a cascade effect, which is based on the mutual independent synthesis of other cytokines. The developing inflammatory process is controlled by interconnected pro-inflammatory cytokines.
What are cytokines
Cytokines are a large group of regulatory proteins whose molecular weight ranges from 15 to 25 kDa (a kilodalton is an atomic mass unit). They act as mediators of intercellular signaling. Their characteristic feature is the transmission of information between cells over short distances. They are involved in the control of key life processes of the body. They are responsible for starting proliferation, i.e. the process of cell multiplication, followed by their differentiation, growth, activity and apoptosis. Cytokines determine the humoral and cellular phase of the immune response.
Cytokines can be considered as a kind of immune system hormones. Among other properties of these proteins, in particular, the ability to influence the energy balance of the body through changes in appetite and metabolic rate, influence on mood, functions and structures of the cardiovascular system, and increased drowsiness are distinguished.
Particular attention should be paid to pro-inflammatory and anti-inflammatory cytokines. The predominance of the former leads to an inflammatory reaction with fever, accelerated respiratory rate and leukocytosis. Others have the advantage of generating an anti-inflammatory response.
Features of cytokines
Main characteristics of cytokines:
- redundancy- the ability to produce the same effect
- pliotropia- the ability to influence different types of cells and cause different actions in them
- synergy- interaction
- induction positive and negative feedback stages
- antagonism– Mutual blocking of action effects
Cytokines and their effect on other cells
Cytokines act in particular on:
- B lymphocytes are cells of the immune system responsible for the humoral immune response, i.e. production of antibodies;
- T-lymphocytes - cells of the immune system responsible for the cellular immune response; they produce, in particular, Th1 and Th2 lymphocytes, between which antagonism is observed; Th1 support cell response and Th2 humoral response; Th1 cytokines negatively affect the development of Th2, and vice versa;
- NK cells - a group of cells of the immune system that is responsible for the phenomena of natural cytotoxicity (toxic effects on cytokines that do not require stimulation of specific mechanisms in the form of antibodies);
- Monocytes are morphological elements of the blood, they are called white blood cells;
- Macrophages are a population of cells in the immune system that comes from blood monocyte precursors; they act both in the processes of innate immunity and acquired (adaptive);
- Granulocytes are a type of white blood cells that exhibit the properties of phagocytes, which should be understood as the ability to absorb and destroy bacteria, dead cells, and some viruses.
Pro-inflammatory cytokines
Pro-inflammatory cytokines participate in the regulation of the immune response and hematopoiesis (the process of production and differentiation of morphotic blood elements) and initiate the development of an inflammatory reaction. They are often called immunotransmitters.
The main pro-inflammatory cytokines include:
- TNF or tumor necrosis factor, formerly called kektsin. Under this name is a group of proteins that determine the activity of lymphocytes. They can trigger apoptosis, the natural process of programmed death of cancer cells. TNF-α and TNF-β are isolated.
- IL-1, i.e. interleukin 1. It is one of the main regulators of the inflammatory immune response. Particularly actively involved in inflammatory reactions of the intestine. Among its 10 varieties, IL-1α, IL-1β, IL-1γ are distinguished. It is currently described as interleukin 18.
- IL-6, i.e. interleukin 6, which has a pleiotropic or multidirectional effect. Its concentration increases in the serum of patients with ulcerative colitis. It stimulates hematopoiesis, showing synergy with interleukin 3. Stimulates the differentiation of B-lymphocytes into plasma cells.
Anti-inflammatory cytokines
Anti-inflammatory cytokines reduce the inflammatory response by suppressing the production of pro-inflammatory cytokines by monocytes and macrophages, especially IL-1, IL-6, IL-8.
Among the main anti-inflammatory cytokines, in particular, IL-10 is mentioned, i.e. interleukin 10 (a factor that inhibits the synthesis of cytokines), IL 13, IL 4, which, as a result of the induction of the secretion of cytokines that affect hematopoiesis, has a positive effect on the production of blood cells.
A.A. Almabekova, A.K. Kusainova, O.A. Almabekov
Asfendiyarov Kazakh National medical university, Department of Chemistry Almaty Technological University Department of Chemistry, Chemical Engineering and Ecology
DEVELOPMENT OF NEW FIRE-RESISTANT COMPOSITE MATERIALS
Resume: Attention of the authors of this article attracted polyimides based on the dianhydrides of aryl-alicyclic fluorine-containing polyheterocycles. These compounds have unique properties, such as high thermal and fire resistance, chemical resistance, solubility, which along with other positive characteristics makes them indispensable in modern technology. For this purpose, composite materials based on fluorine-containing aryl-alicyclic polyimides have been developed, optimal conditions for obtaining epoxy compounds of aryl-alicyclic structure as hardeners using lignosulfonate have been found, and the physicochemical, electrical and thermal properties of synthesized polyimide have been studied.
Keywords: dianhydrides, diamines, polycondensation, epoxy compounds, polyimide, thermoplasticity, fire resistance, viscosity.
Kazakh National Medical University named after S.D. Asfendiyarova, Department of Psychiatry and Narcology, Scientific Clinical Diagnostic Laboratory
LABORATORY DIAGNOSIS OF CYTOKINES (REVIEW)
In this review, much attention is paid to the key and currently relevant issues of the content of cytokines in various biological fluids in assessing the functional activity of immunocompetent cells and the regulation of the immune response. Key words: cytokines, immunochemistry.
Cytokines.
Cytokines are currently considered as protein-peptide molecules produced by various cells of the body and carrying out intercellular and intersystem interactions. Cytokines are universal regulators of the cell life cycle; they control the processes of differentiation, proliferation, functional activation, and apoptosis of the latter. Cytokines produced by cells of the immune system are called immunocytokines; they represent a class of soluble peptide mediators of the immune system necessary for its development, functioning and interaction with other body systems (Kovalchuk L.V. et al., 1999).
As regulatory molecules, cytokines play an important role in the implementation of innate and adaptive immunity reactions, ensure their interconnection, control hematopoiesis, inflammation, wound healing, the formation of new blood vessels (angiogenesis), and many other vital processes. Currently, there are several different classifications of cytokines, taking into account their structure, functional activity,
origin, type of cytokine receptors. Traditionally, in accordance with biological effects, it is customary to distinguish the following groups of cytokines.
1) Interleukins (IL-1 - IL-18) - secretory regulatory proteins of the immune system that provide mediator interaction in
the immune system and its relationship with other body systems;
2) Interferons (IFNa, IFNr, IFNy) - antiviral proteins with a pronounced immunoregulatory and antitumor effect;
3) Tumor necrosis factors (TNFa, TNFor - lymphotoxin) - cytokines with cytotoxic and regulatory action;
4) Colony-stimulating factors (CSF) - growth and differentiation stimulators of hematopoietic cells (GM-CSF, G-CSF, M-CSF);
5) Chemokines - chemoattractants for leukocytes;
6) Growth factors - regulators of growth, differentiation and functional activity of cells of various tissue affiliations (fibroblast growth factor, endothelial cell growth factor, epidermal growth factor) and transforming growth factor - TGFr. Cytokines differ in structure, biological activity, and a number of other features, but they have common properties characteristic of this class of peptides. Typically, cytokines are glycosylated polypeptides of medium molecular weight (less than 30 kD). Cytokines are produced by activated cells at a low concentration for a short time, and their synthesis always begins with gene transcription. Cytokines exert their biological effect on cells through receptors on the surface of target cells. Binding of cytokines to the corresponding receptor leads to cell activation, their proliferation, differentiation or death.
Cytokines exert their biological action predominantly locally, working on the principle of a network. They can act in concert and cause a cascade reaction, sequentially inducing the synthesis of some cytokines by others. Such a complex interaction of cytokines is necessary for the formation of inflammation and the regulation of immune responses. An example of the synergistic interaction of cytokines is the stimulation of inflammatory reactions of IL-1, IL-6 and TNF, as well as the synthesis of IgE by the combined action of IL-4, IL-5 and IL-13. The antagonistic interaction of cytokines can also be a negative regulatory mechanism for controlling the development of an inflammatory reaction and the synthesis of pro-inflammatory and anti-inflammatory cytokines (inhibition of IL-6 production in response to an increase in TNF concentration). Cytokine regulation of target cell functions can be carried out by an autocrine, paracrine or endocrine mechanism. The cytokine system includes producer cells; soluble cytokines and their antagonists; target cells and their receptors. Cells-producers:
I. The main group of cells producing cytokines in the immune system are lymphocytes.
ThO produce a wide range of cytokines at very low concentrations.
Th1 produce IL-2, IFN-a, IL-3, TNF-a, which are necessary for the development of cellular immunity reactions (HRT, antiviral,
antitumor cytotoxicity, etc.) A set of cytokines secreted by Th2 (IL-4, IL-5, IL-6, IL-10, IL-13, IL-3) determines the development of the humoral immune response. In recent years, a subpopulation of Th3 has been described that produce TGFβ, which suppresses the function of both Th1 and Th2.
T-cytotoxic (CD8+), B-lymphocytes, natural killers are weak producers of cytokines.
II. Cells of the macrophage-monocyte series produce cytokines that initiate the immune response and participate in the inflammation and regeneration reactions.
III. Cells not related to the immune system: cells of the connective tissue, epithelium, endothelium spontaneously, without antigenic stimulation, secrete cytokines that support the proliferation of hematopoietic cells, and autocrine growth factors (FGF, EGF, TFRR, etc.).
The immune status is a complex indicator of the state of the immune system, it is a quantitative and qualitative characteristic of the state
functional activity of the organs of the immune system and some non-specific mechanisms of antimicrobial protection. Methods for determining cytokines. Determination of the content of cytokines in various biological fluids is of great importance in assessing the functional activity
immunocompetent cells and regulation of the immune response. In some cases (septic shock, bacterial meningitis), when cytokines, in particular TNF-a, acts as a leading factor in pathogenesis, the determination of its content in the blood or cerebrospinal fluid becomes the main method of immunological diagnostics.
Sometimes the level of cytokines is determined for the purpose of differential diagnosis. For example, in bacterial meningitis, TNFα is detected in the cerebrospinal fluid, while in viral meningitis, as a rule, only IL-1 is found in it. However, the determination of the presence of cytokines in blood serum and other biological fluids may give negative results due to the peculiarities of these peptides. Being mainly short-lived regulators, cytokines have a short half-life (up to 10 min). Some cytokines are contained in the blood in extremely low concentrations, accumulating mainly in the focus of inflammation, in addition, the biological activity of cytokines can be masked when they bind to inhibitor molecules circulating in the blood.
There are three different approaches to the quantitative determination of cytokines: immunochemical (ELISA), bioassay and molecular biological tests. Biological testing is the most
sensitive method, but inferior in specificity to ELISA. There are 4 types of biotesting: by cytotoxic effect, by induction of proliferation, by induction of differentiation and by antiviral effect. According to the ability to induce the proliferation of target cells, the following cytokines are biotested: 1b-1, 1b-2, 1b-4, 1b-5, 1b-6, 1b-7. According to the cytotoxic effect on sensitive target cells ^929), Tn-a and TNF-p are tested. SHI-y is tested for the ability to induce the expression of IHA II molecules on target cells. 8 is tested for the ability to enhance neutrophil chemotaxis. Biotests are used more for research purposes or to confirm ELISA results.
The determination of cytokine in blood serum and other biological materials using solid-phase ELISA has become more widespread. The study is carried out in accordance with the protocol attached to the diagnostic test system. The most commonly used variant of the sandwich ELISA, which consists in the following: one type of mAb to a specific cytokine is immobilized on the inner surface of the wells of the assay plates. The test material and the appropriate standards and controls are added to the wells of the tablet. After incubation and washing, second mAbs are added to the wells to another epitope of this cytokine, conjugated with an indicator enzyme (horseradish peroxidase). After incubation and washing, a substrate-hydrogen peroxide with a chromogen is introduced into the cells. During the enzymatic reaction, the color intensity of the wells changes, which is measured on an automatic plate photometer.
ELISA with the use of mAb against individual epitopes in the cytokine molecule is characterized by high sensitivity and specificity, in addition, the advantage of the method is an objective automated recording of results. However, this method is also not without drawbacks, since the detection of the presence of cytokine molecules is not yet an indicator of their biological activity, the possibility of false positive results due to
due to cross-reacting antigenic epitopes, the use of ELISA does not allow the determination of cytokines in the composition of immune complexes.
ELISA differs from biotesting in lower sensitivity with high specificity and reproducibility. A cytokine is detected by its ability to bind to two different monoclonal antibodies directed against two different antigenic epitopes in the cytokine molecule. For example, the streptavidin-enzyme-enzyme substrate complex is used. However, the ability of most cytokines to form complexes with serum proteins, etc. can significantly distort the results of quantitative determination of cytokine levels. Molecular biological methods make it possible to determine the expression of cytokine genes in the material under study, i.e. the presence of the corresponding mRNA. Reverse transcriptase polymerase chain reaction (RT-PCR) is considered the most sensitive. Reverse transcriptase (revertase) is used to make cDNA copies from mRNA isolated from cells. The amount of cDNA reflects the initial amount of mRNA and indirectly reflects the activity of the production of this cytokine.
induced by mitogens: Con A, PGA, LPS. Interpretation of the data over time makes it possible to predict the further course in organ-specific autoimmune diseases, in multiple sclerosis, in assessing the effectiveness of the applied methods of tumor immunotherapy, etc.
Testing for biological effects is generally not sensitive enough and sometimes not informative enough. The presence of inhibitor or antagonist molecules in the same biological fluid may mask the biological activity of cytokines. At the same time, different cytokines often exhibit the same biological activity. In addition, the performance of biological tests requires special additional equipment, is carried out under non-standard conditions, and is used primarily for research purposes. Conclusion.
Thus, at present there is no doubt that cytokines are the most important factors of immunopathogenesis. The study of the level of cytokines allows obtaining information about the functional activity of various types of immunocompetent cells, the ratio of the activation processes of T-helper types I and II, which is very important in the differential diagnosis of a number of infectious and immunopathological processes.
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A.Sh. Oradova, K.Z. Saduakasova, S.D. Lesova
S.Zh. Asfendiyarov atyndagy K, azats ¥lttyts medicine university Narcology zhene psychiatry departments, gylym clinics-diagnostics zertkhana
CYTOKINNYN, ZERTKHANALSHCH DIAGNOSTICS
Tushn: Sholuy bul ulken nazar man, yzdy belshgen jene sura; kekeikesp K; a3ipri ya; ytta er TYrli biology; suyshtyk; tarda immuno kuzyrly zhasushalardy functional; belsendshkt bagalauda cytokinderdsch mazmuniya zhene immunodi zhauaptyn, retteuk
TYYindi sezder: cytokine, immunity; tysty chemistry.
A.Sh. Oradova, K.Z. Saduakasova, S.D. Lesova
Asfendiyarov Kazakh National medical university, Department of Psychiatry and Narcology, Scientific Clinical and Diagnostic Laboratory
LABORATORY DIAGNOSIS OF CYTOKINES
Resume: In this review, paid great attention to critical and emerging issues currently cytokine content in various biological fluids in the assessment of the functional activity of immune cells and the regulation of the immune response. Keywords: cytokines, immunochemistry.
UDC 616.831-005.1-056:616.12-008.331.1
A.Sh. Oradova, A.D. Sapargaliyeva, B.K. Dyusembaev
Kazakh National Medical University named after S.D. Asfendiyarova, Department of Pathological Anatomy
MOLECULAR MARKERS FOR THE DEVELOPMENT OF ISCHEMIC STROKE (REVIEW)
Recently, a significant number of studies have been devoted to the search for hereditary factors predisposing to the development of cerebrovascular diseases. One of the main directions in these studies is the study of the role of candidate genes. In this review, we systematize the results of recent molecular genetic studies on the relationship between various classes of “candidate genes” and the risk of ischemic stroke in humans. Key words: ischemic stroke, candidate genes.
At present, the role of such risk factors for the development of ischemic stroke, such as arterial hypertension, atherosclerosis, cardiac arrhythmias, heart attack, smoking, diabetes mellitus, lipid metabolism disorders, changes in the hemostatic system, the use of oral contraceptives, abuse of
alcohol, etc. It is known that the severity of ischemic stroke increases with a combination of several risk factors, among which arterial hypertension, hypercholesterolemia, an increase in low-density lipoprotein levels, and smoking are significant. Introduction into clinical practice of rational
A. Interferons (IFN):
1. Natural IFN (1 generation):
2. Recombinant IFN (2nd generation):
a) short action:
IFN a2b: intron-A
IFN β: Avonex and others.
(pegylated IFN): peginterferon
B. Interferon inducers (interferonogens):
1. Synthetic- cycloferon, tiloron, dibazol and etc.
2. Natural- ridostin, etc.
AT. Interleukins : recombinant interleukin-2 (roncoleukin, aldesleukin, proleukin, ) , recombinant interleukin 1-beta (betaleukin).
G. colony stimulating factors (molgramming, etc.)
Peptide preparations
Thymic peptide preparations .
Peptide compounds produced by the thymus gland stimulate the maturation of T-lymphocytes(thymopoietins).
With initially low levels, preparations of typical peptides increase the number of T-cells and their functional activity.
The founder of thymic preparations of the first generation in Russia was Taktivin, which is a complex of peptides extracted from the thymus of cattle. Thymic peptide complex preparations also include Timalin, Timoptin and others, and to those containing thymus extracts - Timimulin and Vilozen.
Preparations of peptides from bovine thymus thymalin, thystimulin administered intramuscularly and taktivin, timoptin- under the skin, mainly in case of insufficiency of cellular immunity:
With T-immunodeficiencies,
viral infections,
For the prevention of infections during radiation therapy and chemotherapy of tumors.
The clinical efficacy of first-generation thymic preparations is not in doubt, but they have one drawback: they are an undivided mixture of biologically active peptides that are rather difficult to standardize.
Progress in the field of drugs of thymic origin went along the line of creating drugs of the II and III generations - synthetic analogues of natural thymus hormones or fragments of these hormones with biological activity.
Modern drug Imunofan - hexapeptide, a synthetic analogue of the active center of thymopoietin, is used for immunodeficiencies, tumors. The drug stimulates the formation of IL-2 by immunocompetent cells, increases the sensitivity of lymphoid cells to this lymphokine, reduces the production of TNF (tumor necrosis factor), has a regulatory effect on the production of immune mediators (inflammation) and immunoglobulins.
Bone marrow peptide preparations
Myelopid obtained from a culture of bone marrow cells of mammals (calves, pigs). The mechanism of action of the drug is associated with stimulation of the proliferation and functional activity of B- and T-cells.
In the body, the target of this drug are B-lymphocytes. In violation of immuno- or hematopoiesis, the introduction of myelopide leads to an increase in the overall mitotic activity of bone marrow cells and the direction of their differentiation towards mature B-lymphocytes.
Myelopid is used in the complex therapy of secondary immunodeficiency states with a predominant lesion of the humoral immunity, for the prevention of infectious complications after surgical interventions, injuries, osteomyelitis, nonspecific pulmonary diseases, chronic pyoderma. Side effects of the drug are dizziness, weakness, nausea, hyperemia and soreness at the injection site.
All drugs in this group are contraindicated in pregnant women, myelopid and imunofan are contraindicated in the presence of Rhesus conflict between mother and fetus.
Immunoglobulin preparations
Human immunoglobulins
a) Immunoglobulins for intramuscular injection
Non-specific: normal human immunoglobulin
Specific: immunoglobulin against human hepatitis B, human antistaphylococcal immunoglobulin, human tetanus immunoglobulin, human immunoglobulin against tick-borne encephalitis, human immunoglobulin against rabies virus, etc.
b) Immunoglobulins for intravenous administration
Non-specific: normal human immunoglobulin for intravenous administration (gabriglobin, immunovenin, intraglobin, humaglobin)
Specific: immunoglobulin against human hepatitis B (neohepatect), pentaglobin (contains antibacterial IgM, IgG, IgA), immunoglobulin against cytomegalovirus (cytotect), human immunoglobulin against tick-borne encephalitis, anti-rabies IG, etc.
c) Immunoglobulins for oral administration: immunoglobulin complex preparation (CIP) for enteral use in acute intestinal infections; anti-rotavirus immunoglobulin for oral administration.
Heterologous immunoglobulins:
anti-rabies immunoglobulin from horse serum, anti-gangrenous polyvalent horse serum, etc.
Preparations of nonspecific immunoglobulins are used for primary and secondary immunodeficiencies, preparations of specific immunoglobulins - for relevant infections (for therapeutic or prophylactic purposes).
Cytokines and preparations based on them
The regulation of the developed immune response is carried out by cytokines - complex complex of endogenous immunoregulatory molecules, which are the basis for creating a large group of both natural and recombinant immunomodulatory drugs.
Interferons (IFN):
1. Natural IFN (1 generation):
Alphaferons: human leukocyte IFN, etc.
Betaferons: human fibroblastic IFN, etc.
2. Recombinant IFN (2nd generation):
a) short action:
IFN a2a: reaferon, viferon, etc.
IFN a2b: intron-A
IFN β: Avonex and others.
b) prolonged action(pegylated IFN): peginterferon (IFN a2b + Polyethylene glycol), etc.
The main direction of action of IFN drugs is T-lymphocytes (natural killers and cytotoxic T-lymphocytes).
Natural interferons are obtained in a culture of donor blood leukocyte cells (in a culture of lymphoblastoid and other cells) under the influence of an inducer virus.
Recombinant interferons are produced by a genetic engineering method - by cultivating bacterial strains containing in their genetic apparatus an integrated recombinant human interferon gene plasmid.
Interferons have antiviral, antitumor and immunomodulatory effects.
As antiviral agents, interferon preparations are most effective in the treatment of herpetic eye diseases (locally in the form of drops, subconjunctival), herpes simplex with localization on the skin, mucous membranes and genitals, herpes zoster (locally in the form of a hydrogel-based ointment), acute and chronic viral hepatitis B and C (parenterally, rectally in suppositories), in the treatment and prevention of influenza and SARS (intranasally in the form of drops). In HIV infection, recombinant interferon preparations normalize immunological parameters, reduce the severity of the disease in more than 50% of cases, cause a decrease in the level of viremia and the content of serum markers of the disease. In AIDS, combination therapy with azidothymidine is carried out.
The antitumor effect of interferon preparations is associated with an antiproliferative effect and stimulation of the activity of natural killers. IFN-alpha, IFN-alpha 2a, IFN-alpha-2b, IFN-alpha-n1, IFN-beta are used as antitumor agents.
IFN-beta-lb is used as an immunomodulator in multiple sclerosis.
Interferon preparations cause similar side effects. Characteristic - influenza-like syndrome; changes from the side of the central nervous system: dizziness, blurred vision, confusion, depression, insomnia, paresthesia, tremor. From the gastrointestinal tract: loss of appetite, nausea; on the part of the cardiovascular system, symptoms of heart failure are possible; from the urinary system - proteinuria; from the hemopoietic system - transient leukopenia. Rash, itching, alopecia, temporary impotence, nosebleeds may also occur.
Interferon inducers (interferonogens):
1. Synthetic - cycloferon, tiloron, poludan, etc.
2. Natural - ridostin, etc.
Interferon inductors are drugs that enhance the synthesis of endogenous interferon. These drugs have a number of advantages over recombinant interferons. They do not have antigenic activity. Stimulated synthesis of endogenous interferon does not cause hyperinterferonemia.
Tiloron(amiksin) refers to low molecular weight synthetic compounds, is an oral interferon inducer. It has a wide spectrum of antiviral activity against DNA and RNA viruses. As an antiviral and immunomodulatory agent, it is used for the prevention and treatment of influenza, SARS, hepatitis A, for the treatment of viral hepatitis, herpes simplex (including urogenital) and herpes zoster, in the complex therapy of chlamydial infections, neuroviral and infectious-allergic diseases, with secondary immunodeficiencies. The drug is well tolerated. Possible dyspepsia, short-term chills, increased overall tone, which does not require discontinuation of the drug.
Poludan is a biosynthetic polyribonucleotide complex of polyadenylic and polyuridylic acids (in equimolar ratios). The drug has a pronounced inhibitory effect on herpes simplex viruses. It is used in the form of eye drops and injections under the conjunctiva. The drug is prescribed for adults for the treatment of viral eye diseases: herpetic and adenovirus conjunctivitis, keratoconjunctivitis, keratitis and keratoiridocyclitis (keratouveitis), iridocyclitis, chorioretinitis, optic neuritis.
Side effects occur rarely and are manifested by the development of allergic reactions: itching and sensation of a foreign body in the eye.
Cycloferon- low molecular weight interferon inducer. It has antiviral, immunomodulatory and anti-inflammatory effects. Cycloferon is effective against tick-borne encephalitis, herpes, cytomegalovirus, HIV, etc. viruses. It has an antichlamydial effect. Effective in systemic connective tissue diseases. The radioprotective and anti-inflammatory effect of the drug was established.
Arbidol is prescribed orally for the prevention and treatment of influenza and other acute respiratory viral infections, as well as for herpetic diseases.
Interleukins:
recombinant IL-2 (aldesleukin, proleukin, roncoleukin ) , recombinant IL-1beta ( betaleykin).
Cytokine preparations of natural origin, containing a fairly large set of cytokines of inflammation and the first phase of the immune response, are characterized by a multifaceted effect on the human body. These drugs act on cells involved in inflammation, regeneration processes, and the immune response.
Aldesleukin- recombinant analogue of IL-2. It has an immunomodulatory and antitumor effect. Activates cellular immunity. Enhances the proliferation of T-lymphocytes and IL-2-dependent cell populations. Increases the cytotoxicity of lymphocytes and killer cells that recognize and destroy tumor cells. Enhances the production of interferon gamma, TNF, IL-1. Used for kidney cancer.
Betaleukin- recombinant human IL-1 beta. Stimulates leukopoiesis and immune defense. It is administered under the skin or intravenously in purulent processes with immunodeficiency, with leukopenia as a result of chemotherapy, with tumors.
Roncoleukin- a recombinant preparation of interleukin-2 - is administered intravenously for sepsis with immunodeficiency, as well as for kidney cancer.
Colony stimulating factors:
Molgramostim(Leikomax) is a recombinant preparation of human granulocyte-macrophage colony-stimulating factor. Stimulates leukopoiesis, has immunotropic activity. It enhances the proliferation and differentiation of precursors, increases the content of mature cells in the peripheral blood, the growth of granulocytes, monocytes, macrophages. Increases the functional activity of mature neutrophils, enhances phagocytosis and oxidative metabolism, providing mechanisms for phagocytosis, increases cytotoxicity against malignant cells.
Filgrastim(Neupogen) is a recombinant preparation of human granulocyte colony stimulating factor. Filgrastim regulates the production of neutrophils and their entry into the blood from the bone marrow.
Lenograstim- recombinant preparation of human granulocyte colony stimulating factor. It is a highly purified protein. It is an immunomodulator and a leukopoiesis stimulator.
Synthetic immunostimulants: levamisole, polyoxidonium isoprinosine, galavit.
Levamisole(decaris), an imidazole derivative, is used as an immunostimulant, as well as an antihelminthic agent for ascariasis. The immunostimulatory properties of levamisole are associated with an increase in the activity of macrophages and T-lymphocytes.
Levamisole is prescribed orally for recurrent herpetic infections, chronic viral hepatitis, autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease). The drug is also used for tumors of the large intestine after surgical, radiation or drug therapy of tumors.
Isoprinosine- a drug containing inosine. Stimulates the activity of macrophages, the production of interleukins, the proliferation of T-lymphocytes.
Assign inside for viral infections, chronic infections of the respiratory and urinary tract, immunodeficiencies.
Polyoxidonium- synthetic water-soluble polymer compound. The drug has an immunostimulating and detoxifying effect, increases the body's immune resistance against local and generalized infections. Polyoxidonium activates all factors of natural resistance: cells of the monocyte-macrophage system, neutrophils and natural killers, increasing their functional activity at initially reduced levels.
Galavit is a derivative of phthalhydrazide. The peculiarity of this drug is the presence of not only immunomodulatory, but also pronounced anti-inflammatory properties.
Drugs of other pharmacological classes with immunostimulatory activity
1. Adaptogens and herbal preparations (phytopreparations): preparations of echinacea (immunal), eleutherococcus, ginseng, rhodiola rosea, etc.
2. Vitamins: ascorbic acid (vitamin C), tocopherol acetate (vitamin E), retinol acetate (vitamin A) (see section "Vitamins").
Echinacea preparations have immunostimulating and anti-inflammatory properties. When taken orally, these drugs increase the phagocytic activity of macrophages and neutrophils, stimulate the production of interleukin-1, the activity of T-helpers, and the differentiation of B-lymphocytes.
Echinacea preparations are used for immunodeficiencies and chronic inflammatory diseases. In particular, immunal administered orally in drops for the prevention and treatment of acute respiratory infections, as well as together with antibacterial agents for infections of the skin, respiratory and urinary tract.
General principles for the use of immunostimulants in patients with secondary immunodeficiencies
The most reasonable use of immunostimulants seems to be in immunodeficiencies, manifested by increased infectious morbidity. The main target of immunostimulating drugs is secondary immunodeficiencies, which are manifested by frequent recurrent, difficult-to-treat infectious and inflammatory diseases of all localizations and any etiology. At the heart of each chronic infectious and inflammatory process are changes in the immune system, which are one of the reasons for the persistence of this process.
Immunomodulators are prescribed in complex therapy simultaneously with antibiotics, antifungal, antiprotozoal or antiviral agents.
· When carrying out immunorehabilitation measures, in particular in case of incomplete recovery after an acute infectious disease, immunomodulators can be used as monotherapy.
· It is advisable to use immunomodulators against the background of immunological monitoring, which should be carried out regardless of the presence or absence of initial changes in the immune system.
Immunomodulators acting on the phagocytic link of immunity can be prescribed to patients with both identified and undiagnosed immune status disorders, i.e. the basis for their use is the clinical picture.
A decrease in any parameter of immunity, revealed during an immunodiagnostic study in a practically healthy person, not necessarily is the basis for the appointment of immunomodulatory therapy.
Test questions:
1. What are immunostimulants, what are the indications for immunotherapy, what types of immunodeficiency states are divided into?
2. Classification of immunomodulators according to the predominant selectivity of action?
3. Immunostimulants of microbial origin and their synthetic analogues, their pharmacological properties, indications for use, contraindications, side effects?
4. Endogenous immunostimulants and their synthetic analogues, their pharmacological properties, indications for use, contraindications, side effects?
5. Preparations of thymic peptides and bone marrow peptides, their pharmacological properties, indications for use, contraindications, side effects?
6. Immunoglobulin preparations and interferons (IFN), their pharmacological properties, indications for use, contraindications, side effects?
7. Preparations of interferon inducers (interferonogens), their pharmacological properties, indications for use, contraindications, side effects?
8. Preparations of interleukins and colony-stimulating factors, their pharmacological properties, indications for use, contraindications, side effects?
9. Synthetic immunostimulants, their pharmacological properties, indications for use, contraindications, side effects?
10. Drugs of other pharmacological classes with immunostimulatory activity and general principles for the use of immunostimulants in patients with secondary immunodeficiencies?
