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External regulation of immune response

External regulation of immune response. J. Ochotná. Causal treatment. a) Stem cell transplantation for serious congenital disorders of the immune system (some lymphoproliferative and myeloproliferative disorders)

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External regulation of immune response

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  1. External regulation of immune response J. Ochotná

  2. Causal treatment a) Stem cell transplantation • for serious congenital disorders of the immune system (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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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 ...)

  8. 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

  9. 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

  10. 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 causing infection or anaphylactic reactions

  11. 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 of induction anaphylactic reactions

  12. 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 • s a promising approach appears to immunization dendritic cells

  13. Defence against extracellular pathogens

  14. 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)

  15. phagocytes production of 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)

  16. 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

  17. Defence against intracellular pathogens

  18. Defense against intracellular pathogens • bacteria, fungi and unicellular parasites • intracellular parasitism is given by the ability of microorganisms to escape 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-

  19. 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

  20. Anti-viral defence

  21. 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)

  22. 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

  23. 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

  24. Defense against multicelular parasites

  25. Defense against multicelular 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“)

  26. 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 • start of production of cytokines (TNF, TGF, IL-4, 5,6 ...) by mast

  27. 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)

  28. Activation of mast cell

  29. Tumour immunology

  30. 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 (loss of contact inhibition) • growth without stimulating growth factors • immortality (cancer cells have not a limited number of generations as normal cells) • often altered number of chromosomes as frequent chromosomal alteration • TSA ...

  31. 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 MHCgp with fragments of proteins of oncogenic viruses- tumors caused by viruses (EBV, SV40, polyomavirus) • abnormal forms of glycoproteins- sialylation of surface proteins of tumor cells • idiotypes of myeloma and lymphoma- clonotyping TCR and BCR

  32. 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 • canceroembryonal antigen (CEA) - colon cancer 2) melanoma antigens • MAGE-1, Melan-A

  33. 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)

  34. 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)

  35. 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)

  36. 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)

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