External regulation of immune response

J. Ochotná

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

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 following chemotherapy 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

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, NF - 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 k B) 

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 (Inhibition of B lymphocytes, antiidiotype activity, inhibition of cytokines, neutralization of toxins, inhibition of complement activation ...)

Anti-inflammatory and antiallergic treatment

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nonsteroidal anti-inflammatory drugs

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antihistamines

- blocking H1 receptor - reduce the expression of adhesion molecules - reduce the secretion of histamine ...

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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

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products of the immune system

      IL-2 - renal adenocarcinoma

IFN

a

, IFN

b - viral hepatitis, some leukemia Erythropoietin – renal failure G-CSF, GM-CSF – neutropenia Transfer factor (blood donors leukocytes undergoing dialysis)

Thymus hormones

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

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

c) specific immunosuppression

= induction of tolerance to 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

Defence against extracellular pathogens

Defence against extracellular pathogens

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

 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 switching produce IgG1 and IgA isotype after isotype (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)

 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

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 → T H 1 differentiation, production of IFN g and membrane TNF → activation of macrophages and induction of iNOS  plasma cells under the influence of IFN immune complexes containing IgG2 bind to Fc receptors on macrophages and thus stimulate them g produce IgG2 , -

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

Defense against intracellular pathogens

Anti-viral defence

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Anti-viral defence

interferons IFN a - in infected cells is induced production of and IFN (iNOS) b (prevents viral replication and in uninfected cells cause the anti-virus status); IFN g stimulates the conversion to activated macrophages  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)

 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

 effector T C 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

Defense against multicellular parasites

Defense against multicellular parasites

 contact of mast cells, basophils and eosinophils parasite antigens with  T H 2 stimulation under the influence of IL-4 (mast cells and other APC stimulated by parasite)  T H 2 stimulate B cells with BCR-specific parasite antigens  isotype switching under the influence of IL-4 to IgE  IgE bind to Fc e RI on mast cells and basophils („antigen specific receptors“)

 establish of multivalent antigen (multicellular parasite) using the IgE to highafinity Fc receptor for IgE (Fc e RI) aggregation of several molecules Fc e 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 b , IL-4, 5,6 ...)

 in later stages are activated T antibodies of other classes H 1 and are produced  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)

Activation of mast cell

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 ...

Tumor antigens

a) Antigens specific for tumors (TSA)

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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

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 a -fetoprotein (AFP) - hepatom carcinoembryonic antigen (CEA) - colon cancer  2) melanoma antigens MAGE-1, Melan-A

  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)

Anti-tumor immune mechanisms

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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, T H 1 and T C )

 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 T H 1 (IFN g , TNF a )  specific cell-mediated cytotoxic reactivity – T C  activation of T H 2 → support B lymphocytes→ tumor specific antibodies (involved in the ADCC)  tumor cells are destroyed by cytotoxic NK cells (ADCC)

Anti-tumor immune mechanisms

Mechanisms of tumor resistance to the immune system

        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 )