Allergy. Immunodeficiency conditions

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Allergy. Immunodeficiency conditions
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• Allergy is an immune response, which is followed
  by damage of own tissues.
• If damage is followed by such changes in
  organism, that are typical for a disease, than
  allergic diseases arise.
• Allergic diseases is a group of diseases, in
  development base of which damage lies, caused by
  an immune reaction on allergens.
• Allergic diseases are widely spread among people.
  It is considered that they cover about 10 of
  earth population. In different countries these
  sizes vacillate from 1 to 50 and more.

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• The cause of allergic diseases is the allergen,
  the conditions of their appearing are the
  specific peculiarities of the environment and
  state of organism reactivity.
• Allergen is a substance that causes development
  of an allergic reaction.
• Allergens have all properties of antigens
  (macromolecularity, mainly protein nature,
  foreign for a particular organism).
• However allergic reactions can be caused by
  substances of not only antigen nature, but also
  substances, not possessing these properties. To
  this group belong many officinal preparations,
  bacterial products, polysaccharides, simple
  chemical substances (bromine, iodine, chrome,
  nickel). These substances are called haptens.
  While entering the organism they become antigens
  (allergens) only after binding with tissues
  proteins. Herewith complex antigens, which
  sensitize the organism are formed.

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Two groups of allergens

• exogenous allergens
• endogenous allergens (autoallergens).
• Exogenous allergens come into the organism from
  outside
• Endoallergens are formed in the organism

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Allergens classifications According to the
origin exogenous allergens are divided into
following groups

• a) allergens of noninfectious origin
• home
• epidermal
• pollen
• food
• industrial
• officinal

• b) allergens of infectious origin
• bacterial,
• fungous,
• viral

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• Domestic allergens. Main role among them domestic
  dust plays, which includes particles,
  bed-clothes, furniture, bacteria.
• Epidermal allergens. To this group refer scurf,
  wool, birds, fur, fish, scales. Professional
  sensitization by epidermal allergen is observed
  in sheepmen, horsemen, poultry farms workers,
  hairdressers.
• Officinal allergens. Any officinal preparation
  with a little exception causes the development of
  an officinal allergy. Medicines or their
  metabolites are, as usual, haptens. In case of
  sensitization of the organism to one preparation,
  allergic reactions to other medicines, having
  alike chemical structure can arise.

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• Pollen allergens. Allergic diseases are caused by
  shallow plants, pollen. It is called pollinosis.
  The diverse types of pollen can have the general
  allergens, therefore in people, sensitive to one
  type of pollen, a reaction on its other kinds is
  possible.
• Food allergens. Many food products can be by
  allergens. They are usually fish, wheat, beans,
  tomatoes, milk, eggs. Chemical substances added
  to food products (dye-stuffs, antioxidants,
  aromatic and other substances) may also be
  allergens.
• Industrial allergens. The industrial allergens
  for the most are haptens. In each industrial
  production a particular admission of chemical
  matters is used. These are resin, glue and
  covering materials, plastics, dye-stuffs, metals
  and their salts, wood products, latex, perfumer
  substances, washing means, synthetic cloths and
  others.

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• Allergens of infectious origin.
• All the different causative agents of infectious
  diseases and products of their life activity
  cause the development of allergic processes.
• Those infectious diseases, in pathogenesis of
  which allergy plays a leading role, were named
  infectiously allergic. These are all the chronic
  infections (tuberculosis, lepra, brucellosis,
  syphilis, rheumatism, chronic candidosis etc.).
• The widespread allergens are the fungi. Many
  nonpathogenic fungi while entering the organism
  cause sensitization and development of diverse
  allergic diseases (bronchial asthma).
• Such fungi are contained in atmospheric air,
  dwellings, domestic dust, food products. With
  biotechnological development a possibility of
  sensitization on enterprises on production of
  stern squire, vitamins, antibiotics, enzymes
  arises.

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Pathogenesis of allergy reactions

• There are different classifications of allergic
  reactions
• R.A.Cook picked out
• allergic reactions of immediate type and
• allergic reactions of delayed-type or
  hypersensitization of delayed-type

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• In the base of classification the time of
  appearing of reaction after contact with allergen
  has been placed.
• The reactions of immediate type developed during
  15-20 minutes, delayed-type after 1-2 days.
• However it does not envelop all the variety of
  allergy displays. For example, some reactions
  develop over 4-6 or 12-18 hours.
• Therefore the distinctions between allergic
  reactions were interconnected with different
  mechanisms of their development and the
  classifications based on pathogenic principle
  were put together.

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• The classification by P.Gell, R.Coombs is widely
  spread in the world.
• It is based on pathogenic principle. The
  peculiarities of immune mechanisms lay in its
  base.
• In accordance to this classification there are 4
  types of allergic reactions
• anaphylaxic
• cytotoxic
• immune-complex
• delayed hypersensitivity

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Allergy development stages

• Entering into the organism antigen causes its
  sensitization
• Sensitization is an immunological rising of
  organism sensitiveness to antigens (allergens) of
  exogenous or endogenous origin
• According to method of receiving there are active
  and passive sensitizations

• Active sensitization develops in artificial
  introduction or natural penetration of the
  allergen into the organism
• Passive sensitization is reproduced in the
  experiment by introduction of blood plasma or
  lymphoid cells of an actively sensitized donor to
  an intact recipient

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In the development of allergic reaction there
are three stages

• 1. Immunological stage. It covers all the changes
  in immune system during the penetration of an
  allergen into the organism, formation of
  antibodies or sensitized lymphocytes and their
  binding with the repeatedly entering allergen.
• 2. Pathochemical stage. Its sense is in formation
  of biological active substances. The stimulus to
  their formation is the binding of allergen to
  antibodies or sensitized lymphocytes at the end
  of immunological stage.
• 3. Pathophysiological stage. It is described by
  pathogenic action of formed mediators onto cells,
  organs and tissues of the organism with a
  clinical display.

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• In this way the immunological mechanisms lay in
  development base of allergic processes.
• Central cell of immune system is a lymphocyte.
• Lymphocytes are heterogenic according to their
  functions, markers, receptors.
• They develop from a stem cell.
• A lymphoid stem cell will form from it, from
  which T- and B-lymphocytes develop.
• The T-lymphocytes acquire the specific antigen
  receptors, with the help of which they identify
  an antigen and other markers.

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• There are 3 types of T-cells
• T-helpers
• T-suppressors
• T-effectors
• The last ones form sensitized lymphocytes or
  killers, which participate in realization of
  allergic reaction of delayed-type and realize
  cytotoxic action on cell-target.
• The B-lymphocytes produce 5 classes of
  immunoglobulins IgG, IgM, IgA, IgE, IgD.
• These cells during ripening acquire the receptors
  for antigen on their membranes. During binding of
  such B-cells with proper allergens and after the
  signal, received from T-helper, they become
  activated, and proliferation and differentiation
  into antibody producing cells starts.

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• The correlation between two groups of
  subpopulations of T-helpers (Th-1 and Th-2) plays
  an important role in the development of immune
  reaction.
• They are both formed of Th-0 and differ form each
  other by the set of secreted lymphokines and
  quantity of Fc-receptors for immune globulins on
  their surface.
• On Th-2 there are many receptors for immune
  globulins A, M, E, and on Th-1 there are a few of
  them or they are absent.

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• During the activation of Th-1 the formation of
  IL-2 increases, it stimulates the secretion of
  immune globulins A, M and G by B-cells and turns
  on cellular mechanism of immunity.
• Activation of Th-2 leads though IL-4 to changing
  of synthesis of IgE by B-cells to proliferation
  of fat cells and through IL-5 to increasing and
  proliferation of eosinophiles.
• There are antagonistic relationship between these
  two ways.
• The choice of way of activation depends on
  character of allergen.
• Besides that the form of allergen, conditions on
  introduction into organism and its quantity play
  role.

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Anaphylactic type of allergic reactions

• According to anaphylactic type a group of atopic
  diseases
• atopic bronchial asthma
• pollinosis
• atopic dermatitis
• nettle-rash
• food and officinal allergy

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Immunological stage

• IgE and IgG4 are formed as an answer to
  penetrating of allergen into the organism.
• They get fixed on the mast cells and basophiles
  of blood. These cells have on their surface Fc
  receptors for immune globulin. The state of
  sensitization of the organism appears.
• If the same allergen again gets into the organism
  or it still stays in the organism after the first
  penetration, connection of antigen with
  IgE-antibodies occurs.
• The same thing is observed with IgG4. they bind
  with their receptors on basophiles, macrophages,
  eosinophiles, trombocytes.
• Depending on the quantity of molecules of
  IgE-antibodies connected to antigen, quantity of
  antigen we can observe either inhibition of
  activity of the cell or its activation and
  transfer of the process to the next,
  pathochemical stage.

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Pathochemical stage

• Activation of the most and basophile cells leads
  to releasing of different mediators. The process
  of secretion of mediators need energy, thats why
  blocking of energy-formation blocks also
  releasing of mediators.
• A certain role in this process play cyclic
  nucleotides of the cells cAMP and cGMP.
  Secretion of one of the main mediators
  histamine depends on their correlation.
• Many different mediators have been excluded from
  the most cells and basophile leucocytes. Some
  mediators are in the cell in ready form and are
  easily secreted (histamine, serotonin,
  eosinophiles chemotaxic factors).
• Some mediators are formed after stimulation of
  the cell (leukotriens, trombocyte activating
  factors). This mediators act on vessels and
  target-cells, including in the development of
  allergic reaction eosinophiles, trombocytes and
  other cells.
• As a result eosinophiles, neutrophiles, which
  start also to release mediators phosrholipase
  D, histaminase, leukotriens and others come to
  the place of activation of the most cells.

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Histamine

• Histamine is localized in ready form in granules
  of the most cells and basophile leucocytes.
• In the blood of healthy people histamine almost
  totally stays in basophile leucocytes.
• Histamine acts on the tissues cells through the
  receptors of two types H1 and H2.
• Their correlation and spreading on the cells of
  different cells is different. Stimulation of H1
  promotes to contraction of smooth muscles,
  endothelial cells and postcapillary part of
  microcirculation. This leads to increasing of
  permeability of vessels, development of edema and
  inflammation.
• Stimulation of H2 causes the opposite effects.

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• Besides this releasing of histamine from
  basophile leucocytes and from the lungs is
  diminished through them, the function of the
  lymphocytes modulates, formation of migration
  ingibitory factor (MIF) by T-lymphocytes gets
  oppressed, releasing of lysosome enzymes by
  neutrophile leucocytes diminishes as well.
• In many cases the increasing of quantity of
  histamine in blood is observed in the intensive
  stage of bronchial asthma, nettle-rash, officinal
  allergy.

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Heparin

• Heparin is activated after releasing out of the
  most cells.
• It possesses an antitrombine and anticomplementar
  activity.
• Trombocyte activating factor (TAF) is secreted by
  basophiles, lymphocytes, trombocytes and
  endothelial cells.

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• TAF acts on target-cells through corresponding
  receptors
• 1) it causes the aggregation of trombocytes and
  releasing of histamine and serotonin out of them
• 2) it helps to chemotaxis and secretion of
  granular content of eosinophiles and neutrophiles
• 3) it causes spasm of smooth muscles
• 4) it increases permeability of vessels

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Metabolites of arachidone acid

• It is metabolized in two different ways
  cyclooxygenic and lipooxygenic.
• Under the influence of cyclooxygenase
  prostaglandins, tromboxans and prostacycline are
  formed from arachidone acid.
• Under the influence of lipooxygenase leukotriens
  are formed from it.

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• In allergy prostaglandins of F group possess the
  ability to cause contraction of smooth muscles,
  including bronchi, and prostaglandins of E group
  provide the relaxing action.
• Leukotriens cause the spasm of smooth muscles,
  increase secretion of mucous, decrease coronary
  blood flow and power of heart contractions,
  increase chemotaxis of polymorphic-nuclear
  leukocytes, lead to development of prolonged
  bronchial spasm.

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Pathophysiological stage

• Under the influence of mediators the permeability
  of vessels and chemotaxis of neutrophiles and
  eosinophiles increase, which leads to development
  of inflammatory reaction.
• The increasing of permeability of vessels
  promotes the exit of fluid, immunoglobulins and
  complement into tissues.
• With the help of mediators and also through the
  IgE-antibodies, the cytotoxic effect of
  macrophages is activated, secretion of enzymes,
  prostaglandins and leukotriens, trombocyte
  activating factor is stimulated.
• The released mediators cause also a damaging
  action onto cells and connective tissue
  structures.
• Bronchospasm develops in respiratory organs.
• These effects are clinically manifested by
  attacks of bronchial asthma , rhinitis,
  conjunctivitis, nettle-rash, skin itch,
  diarrhea.

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Anaphylactic shock

• Anaphylactic shock develops in severe
  complication.
• Spasm of smooth muscles of internal organs with
  clinical manifestation of bronchospasm (cough,
  expiratory breathlessness), spasm of
  gastro-intestinal tract muscles (spastic pain in
  the whole abdomen, nausea, vomiting, diarrhea),
  spasm of uterus in women (pain below abdomen) are
  observed.
• Spastic phenomena are worsened by edemas of
  mucous covers of internal organs, during the
  edema of larynx the picture of asphyxia may
  develop.
• The arterial pressure is sharply decreased, the
  heart insufficiency, ischemia of brain, seizes
  paralysis develop, danger for the life of the
  patient appears.

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Cytotoxic type of allergic reactions

• Immunological stage. It is called cytotoxic
  because the antibodies that developed to antigen
  of the cell bind to cells and cause their damage
  or even lysis (cytolytic action). For turning on
  of this mechanism cells of tissues have to
  acquire autiallergen properties. Than the
  formation of autoantibodies starts. In this
  process action of chemical substances, usually
  medicines, viruses, microbes onto the cell plays
  a big role. They may change the antigen structure
  of cell membranes. The formed autoantibodies
  belong to IgG and IgM. They connect to
  corresponding antigens of the cells by their
  Fab-fragments.

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• Pathochemical stage. The main mediator of
  cytotoxicity is the activated enzymes of
  complement. Phagocytes release some lyzosome
  enzymes and generate superoxide anion-radical.
• Pathophysiological stage. The damage of the cell
  with the antigen properties may be caused by
  three reasons due to activation of complement,
  the components of which damage the cell membrane
  due to activation of phagocytosis of the cells
  covered with antibodies due to activation of
  T-lymphocytes, natural killers, K-lymphocytes.

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Immune complex type

• Immunological stage. Many exogenous and
  endogenous antigens participate in formation of
  immune complexes. Among them there are officinal
  preparations (penicillin, sulfanilamides,),
  antitoxic vaccines, allogen gamma-globulins, food
  product (milk, egg white), inhalation allergen
  (home dust, fungi). In case of penetration of
  soluble antigen into the organism IgG and IgM
  antibodies are formed. These antibodies can cause
  the formation of precipitate and connection to
  antigen. Immune complex can be formed in tissues
  or in blood flow.
• Patochemical stage. Under the influence of immune
  complexes the following mediators are formed
  fragments C3a, C5a, C4a of the complement,
  lyzosomal enzymes of phagocytes, kinines,
  superoxyde anion-radical.

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• Pathophysiological stage. Usually immune
  complexes are placed on vessels of cannalicular
  apparatus of kidneys, inflammation with
  alteration, exudation and proliferation
  (glomerulonephritis) develops, in case if the
  complexes are placed in the lungs alveolitis
  appears, in skin dermatitis. The inflammation
  may lead to formation of ulcers, hemorrhages,
  thrombosis is possible in the vessels. This type
  of allergic reactions is the prominent one in
  development of serum , some cases of officinal
  and food allergy, some autoallergic diseases
  (rheumatoid arthritis, systemic red lupus
  erythematosus). In case of massive activation of
  complement anaphylactic shock, bronchial asthma
  may develop.

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Allergic reactions of delayed type

• Immunological stage. The cellular mechanism of
  immunity is usually activated in cases of
  insufficiency of effectiveness of humoral
  mechanisms, for example, in case of intracellular
  localization of the antigen (mycobacterium,
  brucella, histoplasma etc.) or when cells are
  antigen themselves. They may microbes, fungi and
  their spores, which get into the organism from
  the outside. The cells of own tissues also may
  acquire the auto allergen properties. This
  mechanism may turn on as a response to formation
  of complex allergens, in case of including
  haptens into proteins, for example, in case of
  contact dermatitis, which appears during the
  contact of the skin with different medicinal,
  industrious and other allergens.

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• The foreign antigen is phagocyted by macrophages
  and get to T-helpers. At the same time
  macrophages secrete IL-1, which stimulates
  T-helpers. The latest excrete the growth factor
  pro-T-lymphocytes IL-2, which activates and
  supports proliferation of antigen stimulated
  T-cells. This process leads to formation of
  sensitized lymphocytes. They belong to
  T-lymphocytes and in the cell membrane they have
  receptors of the antibody type, which are able to
  connect with the antigen. In case of repeated
  penetration of the allergen into the organism it
  binds with the sensitized lymphocytes.

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Pathochemical stage

• This leads to morphological, biochemical and
  functional change in lymphocytes.
• They are presented by blast transformation and
  proliferation, increasing of synthesis of DNA,
  RNA and proteins and secretion of different
  mediators, which are called lymphokines. With the
  help of lymphokines (MIF, interleukines,
  chemotaxic factors, factor of transfer)
  mobilization of different cells (macrophages,
  polymorph-nuclear), increasing of chemotaxic
  activity and placing in the site of allergen
  occur.

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• MIF promotes accumulation of macrophages in the
  site of allergic damage, increases their activity
  and phagocytosis. It takes part in formation of
  granulems during infectious-allergic diseases,
  increase the ability of macrophages to destroy
  certain kinds of bacteria.
• There are several kinds of chemotaxic factors,
  each of which is called chemotaxis of
  leukocytes macrophages, neutrophiles,
  eosinophiles and basophiles.
• Lymphotoxins cause damage and destroying of all
  different target-cells.

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• Interferon is secreted by lymphocytes and under
  the influence of a-interferon and nonspecific
  mitogens. It acts a modulating influence on
  cellular and humoral mechanisms of immune
  reaction.
• Besides lymphokines, lizosome enzymes also
  provide a damaging activity. They are released
  during phagocytosis and destroying of cells.
• Kallikreine-kinine system is also activated.
• Histamine doesnt play a big role in this type
  of allergic reactions.

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Pathophysiological stage

• A particular form of lymphokines (lymphotoxin,
  interferon) shows a cytotoxic action and
  decreases activity of cell. In allergic reaction
  of delayed type damaging action may develop in
  several ways
• 1) direct cytotoxic action of sensitized
  T-lymphocytes on target-cells, which acquired
  autoallergen properties
• 2) cytotoxic activity of T-lymphocytes, mediated
  by lymphotoxin
• 3) releasing of lysosome enzyme, which damage
  tissue structures during phagocytosis.

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• Inflammation that is associated to immune
  reaction by action of mediators is a component
  of allergic reaction of delayed-type.
• Nevertheless inflammation is at the same time a
  factor of damage of function of the organs.
• Allergic reactions of delayed type make the base
  of development of infectious-allergic diseases
  (tuberculosis, lepra, brucellosis, syphilis),
  rejection of transplant, and autoallergic
  diseases (disturbance of nervous system,
  endocrine glands etc.).

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Pseudoallergic reactions

• Pseudoallergy is a pathological process, which is
  clinically similar to allergy but doesnt have an
  immune stage of its development. Pseudoallergy
  differs from a simple one by the absence of first
  (immune) stage. The rest two stages releasing
  of mediators (pathochemical) and
  pathophysiological (stage of clinical
  manifestations) are the same both in
  pseudoallergy and a real one. To pseudoallergic
  reactions refer only processes in the development
  of which the leading role play mediators, which
  are formed also in pathochemical stage of true
  allergic reactions.

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• The reason of pseudoallergy is any substance that
  acts directly on effector cells (fat cells,
  basophiles etc.) or biological fluids and cause
  releasing of mediators from the cells or
  production of them in the fluids.
• Practically most of the allergens can lead to
  development of both allergic and pseudoallergic
  reactions.
• This depends on nature of the substance, its
  phase, frequency of introduction into the
  organism and reactivity of the organism.
• Pseudoallergic reactions usually occur in
  officinal and food intolerance.
• Many remedies more usually lead to development of
  pseudoallergy than true allergy.

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• Clinical picture of pseudoallergic diseases is
  close to one of allergic diseases.
• Development of such pathological processes as
  increasing of permeability of vessels, edema,
  inflammation , spasm of smooth muscles,
  destroying of blood cells lay in the base of this
  clinical picture.
• These processes may be local, organic and
  systemic.
• They are presented by rhinitis, nettle-rash,
  Kvinkes edema, periodical headaches, disturbance
  of gastro-intestinal tract, bronchial asthma,
  vaccine disease, anaphylactic shock and also
  damaging of certain organs.

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Preventing of allergy. Hyposensitization

• Prophylaxis of an allergic disease depends on its
  character and group of the allergens. It consists
  of measures of preventing of penetration of given
  allergen into the organism and preventing of the
  influence of different irritating factors on the
  organism. If sensitization has already occurred
  and allergic diseases has already started, the
  following measures are appropriate.
• 1. Suppression of antibodies and sensitized
  lymphocytes production with the help of immune
  depressants, ionizing radiation, cytostatics,
  specific lymphocyte vaccines and monoclonal
  antibodies.

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• 2. Specific desensitization by Bezredka.
  Desensitization is provided by little doses of
  the antigen, which do not cause severe reactions.
  The doses are introduced repeatedly after certain
  intervals of time, during which produced
  mediators get inactivated in the organism. The
  main dose of the antigen is introduced after
  antibodies binding. This method is effective in
  introduction of foreign medical vaccines.
• 3. Inactivation of biological active substances.
  For this purpose antihistamine preparations,
  inhibitors of proteolytic enzymes etc. are
  introduced.
• 4. Protection of the cells from the influence of
  biological active substance and also normalizing
  of functional disorders in organs and systems
  (narcotic, spasmolytic substances, receptor
  blockers etc.).