External regulation of immune response

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External regulation of immune response
J. Ochotná
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Causal treatment

• a) Stem cell transplantation    
• for serious congenital disorders of the immune
  system and some lymphoproliferative and
  myeloproliferative disorders
• complications infectious complications
                      Graft-versus-host
• obtaining stem cells - collection from shovel hip
  bone                              - from
  umbilical cord blood                             
   - from peripheral blood after stimulation
  with GM-CSF

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• b) Gene therapy
• with a suitable expression vector is introduced
  functional gene (to replace dysfunctional gen)
  into the lymphocytes or stem cells
• used as a treatment for some cases of SCID

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Substitution treatment

• autologous stem cell transplantation
  followingchemotherapy and radiotherapy
• treatment with intravenous immunoglobulin
  (derived from plasma of blood donors)
• substitution of C1 inhibitor for hereditary
  angioedema
• substitution of erythropoietin in patients with
  chronic renal failure
• substitution of G-CSF in agranulocytosis

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Immunomodulation

• medical procedure to adjust the disrupted
  immune function
• Non-specific immunosuppressive therapy
• nonspecific affects not only autoreactive and
  aloreactive                        lymphocytes,
  but also other components of
  immunity (risk of
  reduction antiinfectious and anti-
  tumor immunity)
• used for treatment of autoimmune diseases, severe
  allergic conditions and for organ
  transplantation

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Non-specific immunosuppressive therapy

• corticosteroids - anti-inflammatory,
  immunosuppressive
  effects                    - blocking the
  activity of transcription
  factors (AP-1, NFkB)                   
  - suppress the expression of genes (IL-2,
  IL-1, phospholipase A, MHC
  gp II, adhesion
  molecules)                   - inhibition
  of histamine release from basophils
                     - higher concentrations
  induce apoptosis of
  lymfocytes
• immunosuppressants affecting the metabolism of
  DNA - cyclophosphamide                       
     - methotrexate -
  azathioprine
  

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• immunosuppressant selectively inhibiting T
  lymphocytes - immunosuppressive ATB
  cyclosporine A, tacrolimus,
  rapamycin (suppressing the expression of IL-2 and
  IL-2R in activated T
  lymphocytes)                 - monoclonal
  antibody anti-CD3 (Immunosuppression
  after transplantation, treatment of
  rejection crises)
• immunoglobulins in the immunosuppressive
  indication                  - Polyspecific
  intravenous immunoglobulins                    (I
  nhibition of B lymphocytes, antiidiotype
  activity, inhibition of
  cytokines, neutralization of toxins,
  inhibition of complement activation ...)

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Anti-inflammatory and antiallergic treatment

• nonsteroidal anti-inflammatory drugs
• antihistamines - blocking H1 receptor
                           - reduce the expression
  of adhesion molecules
                           - reduce the secretion
  of histamine ...
• inhibitors of inflammatory cytokine -
  receptor antagonist for IL-1                     
       - monoclonal antibodies against TNF
                           - thalidomide (TNF
  inhibitor)
• enzyme therapy - in the enzyme mixture has a
  major effect
  trypsin and bromelain                           
  - anti-inflammatory
  and immunomodulatory effects

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Non-specific immunostimulant therapy

• synthetic immunomodulators
• Methisoprinol (Isoprinosine) - used in viral
  infections with more
  severe or relapsing course
• bacterial extracts and lysates
• Broncho-Vaxom - prevention of recurrent
  respiratory tract infections
• Ribomunyl
• products of the immune system
• IL-2 - renal adenocarcinoma
• IFNa, IFNb - viral hepatitis, some leukemia
• Erythropoietin renal failure
• G-CSF, GM-CSF neutropenia
• Transfer factor (blood donors leukocytes
  undergoing dialysis)
• Thymus hormones              

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Antigen-specific immunomodulatory therapy

• specific immunomodulation induce an immune
  response or tolerance against a specific antigen
  a) active immunization use of antigen to
  induce an immune response that can later protect
  against a pathogen bearing the antigen (or
  similar antigen)
• immunization vaccines are made from inactivated
  or attenuated microorganisms or their antigens
  (polysaccharide capsule, toxins)
• creates long-term immunity
• activate cellular and antibody immunity
• administration of antigen injectable, oral
• prophylaxis
• risk of infection or anaphylactic reactions

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• b) passive immunization
• natural - transfer of maternal antibodies in
  fetal blood
• therapeutically - the use of animal antibodies
  against various
  toxins (snake toxins, tetanus
  toxin, botulinum toxin)
• prophylaxis - the human immunoglobulin from
  immunized individuals (hepatitis
  A, rabies, tetanus)
                      - Anti-RhD antibodies -
  preventing maternal
  immunization with RhD fetus
• provides a temporary (3 weeks) specific humoral
  immunity
• the risk anaphylactic reactions

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• c) specific immunosuppression induction of
  tolerance against a specific antigen
• ongoing clinical studies
• induction of tolerance by oral administration of
  antigen (treatment of certain autoimmune
  diseases)
• allergen immunotherapy (pollen, insect poisons)
• d) vaccination against cancer
• immunization by dendritic cells

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Defence against extracellular pathogens
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Defence against extracellular pathogens

• bacteria (gram-negative, gram-positive cocci,
  bacilli), unicellular parasites
• for their elimination is necessary opsonization
  (C3b, lectins, antibodies ...)
• neutrophilic granulocytes are chemotactic
  attracting to the site of the infection (C5a, C3a
  and chemotactic products of bacteria)
• absorbed bacteria are destroyed by the
  microbicidal systems (products of NADP-H
  oxidase, hydrolytic enzymes and bactericidal
  substances in lysosomes)

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• phagocytes produce proinflammatory cytokines
  (IL-1, IL-6, TNF) that induce an increase in
  temperature, metabolic response of the organism
  and synthesis of acute phase proteins
• in later stages of infection are stimulated
  antigen-specific mechanisms
• plasma cells initially produce IgM isotype after
  isotype switching produce IgG1 and IgA
  (opsonization)
• sIgA protect against intestinal and respiratory
  infections by bacteria
• bacteria with a polysaccharide capsule may cause
  T-independent IgM antibody production (after the
  establishment to the bacteria activate the
  classical complement path)

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• after infection persist IgG, IgA (protective
  effect) and memory T and B lymphocytes
• in the defense against bacterial toxins apply
  neutralizing antibodies (Clostridium tetani and
  botulinum ...)
• "indirect toxins - bacterial Lipopolysaccharide
  (LPS) stimulates big number of monocytes to
  release TNF, which can cause septic shock
• extracellular bacterial infections are especially
  at risk individuals with disorders in the
  function of phagocytes, complement and antibody
  production

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Defence against intracellular pathogens
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Defense against intracellular pathogens

• bacteria, fungi and unicellular parasites
• intracellular parasites are resistant to the
  microbicidal mechanisms of phagocytes
• macrophages, which absorbed them, produce IL-12 ?
  TH1 differentiation, production of IFNg and
  membrane TNF ? activation of macrophages and
  induction of iNOS
• plasma cells under the influence of IFNg produce
  IgG2, immune complexes containing IgG2 bind to
  Fc receptors on macrophages and thus stimulate
  them-

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• in the defense against intracelular parasites,
  which escape from phagolysosomes apply TC
  lymphocytes
• intracellular microorganisms infections are at
  risk individuals with certain disorders of
  phagocytes and defects of T lymphocytes

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Defense against intracellular pathogens
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Anti-viral defence
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Anti-viral defence

• interferons - in infected cells is induced
  production of IFNa and IFNb (prevents viral
  replication and in uninfected cells cause the
  anti-virus status) IFNg stimulates the
  conversion to activated macrophages (iNOS)
• NK cells - ADCC (Antibody-dependent cell-mediated
  cytotoxicity) cytotoxic reaction depends on the
  antibodies the NK-lymphocyte recognizes cell
  opsonized with IgG by stimulation Fc receptor
  CD16 and then activate cytotoxic mechanisms
  (degranulation)
• infected macrophages produce IL-12 (a strong
  activator of NK cells)

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• in the defense against cytopathic viruses mostly
  applied antibodies
• sIgA inhibit mucosal adhesion of viruses (defense
  against respiratory viruses and enteroviruses)
• neutralizing IgG and IgM antibodies activate the
  classical way of complement, which is capable of
  some viruses lysis
• IgA and IgG derived in viral infection have a
  preventive effect in secondary infection

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• effector TC lymphocytes destroy infected cells in
  direct contact (granzym/perforin FasL) and by
  produced cytokines (lymfotoxin)
• some viruses after infection integrate into the
  host genome, where persist for years (varicella
  zoster, EBV, papillomavirus)
• by these infections are at risk individuals with
  T lymphocyte immunodeficiency and with combined
  immune disorders
• increased susceptibility to herpes infections in
  individuals with dysfunction of NK cells

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Defense against multicellular parasites
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Defense against multicellular parasites

• contact of mast cells, basophils and eosinophils
  with parasite antigens
• TH2 stimulation under the influence of IL-4 (mast
  cells and other APC stimulated by parasite)
• TH2 stimulate B cells with BCR-specific parasite
  antigens
• isotype switching under the influence of IL-4 to
  IgE
• IgE bind to FceRI on mast cells and basophils
  (antigen-specific receptors)

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• establish of multivalent antigen (multicellular
  parasite) using the IgE to highafinity Fc
  receptor for IgE (Fc?RI) aggregation of several
  molecules Fc?RI
• initiate mast cell degranulation (cytoplasmic
  granules mergers with the surface membrane and
  release their contents)
• activation of arachidonic acid metabolism
  (leukotriene C4, prostaglandin PGD2) -
  amplification of inflammatory responses
• cytokine production by mast cell (TNF, TGF?,
  IL-4, 5,6 ...)

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• in later stages are activated TH1 and are
  produced antibodies of other classes
• eosinophils fagocyte complexes of parasitic
  particles with IgE via their receptors for IgE
• eosinophils use against parasites extracellular
  bactericidal substances released from granules
  (eosinophil cationic protein, protease)

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Activation of mast cell
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Anti-tumour immunology
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• Malignant transformation
• failure of regulation of cell division and
  regulation of "social" behavior of the cells
• the uncontrollable proliferation, dissemination
  to other tissues
• mutations in protoonkogenes and antionkogenes
• Tumor cells
• unlimited growth
• growth without stimulating growth factors
• immortality
• often altered number of chromosomes as frequent
  chromosomal alteration
• TSA ...

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Tumor antigens

• Antigens specific for tumors (TSA)
• complexes of MHCgp I with abnormal fragments of
  cellular proteins - chemically induced tumors
  - leukemia with
  chromosomal translocation
• complexes of MHC gp with fragments of proteins of
  oncogenic viruses - tumors caused by viruses
  (EBV, SV40,
  polyomavirus)
• abnormal forms of glycoproteins - sialylation of
  tumor cells
  surface proteins
• idiotypes of myeloma and lymphoma - clonotyping
  TCR
  and BCR

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• b) Antigens associated with tumors (TAA)
• present also on normal cells
• differences in quantity, time and local
  expression
• auxiliary diagnostic markers
• 1) onkofetal antigens
• on normal embryonic cells and some tumor cells
• ?-fetoprotein (AFP) - hepatom
• carcinoembryonic antigen (CEA) - colon cancer
• 2) melanoma antigens
• MAGE-1, Melan-A

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• 3) antigen HER2/neu
• receptor for epithelial growth factor
• mammary carcinoma
• 4) EPCAM
• epithelial adhesion molecule
• metastases
• 5) differentiation antigens of leukemic cells
• present on normal cells of leukocytes linage
• CALLA -acute lymphoblastic leukemia (CD10 pre-B
  cells)

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Anti-tumor immune mechanisms

• Immune control
• tumor cells normally arise in tissues
• and are eliminated by T lymphocytes
• probably wrong hypothesis
• Defensive immune response
• tumor cells are weakly immunogenic
• occurs when tumor antigens are presented to T
  lymphocytes by dendritic cells activated in the
  inflammatory environment
• if tumor cells are detected, in defense may be
  involved non-specific mechanisms (neutrophilic
  granulocytes, macrophages, NK cells) and
  antigen-specific mechanisms (complement
  activating antibodies or ADCC, TH1 and TC)

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• cancer-associated antigens are processed by APC
  and recognized by T lymphocytes in complex with
  HLA I. and II. class with providing costimulus
  signals
• predominance of TH1 (IFN g, TNFa)
• specific cell-mediated cytotoxic reactivity TC
• activation of TH2 ? support B lymphocytes? tumor
  specific antibodies (involved in the ADCC)
• tumor cells are destroyed by cytotoxic NK cells
  (ADCC)

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Anti-tumor immune mechanisms
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Mechanisms of tumor resistance to the immune
system

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• high variability of tumor cells
• low expression of tumor antigens
• sialylation
• tumor cells signals do not provide costimulus ? T
  lymphocyte anergy
• some anticancer substances have a stimulating
  effect
• production of factors inactivating T lymphocytes
• expression of FasL ? T lymphocyte apoptosis
• inhibition of the function or durability
  dendritic cells (NO, IL-10, TGF-b)

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