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IMMUNE REACTIONS prof. Martínková 2006

IMMUNE REACTIONS prof. Martínková 2006. Innate immune response Adaptive immune response. Innate immune response occurs soon after infection:

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IMMUNE REACTIONS prof. Martínková 2006

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  1. IMMUNE REACTIONS prof. Martínková 2006

  2. Innate immune response Adaptive immune response

  3. Innate immune response • occurs soon after infection: • tissue macrophages recognise, by means of specific DNA-encoded receptors specific pathogen-associated molecular patterns (PAMPs) on the microorganisms • release of of cytokines (IL-1 and TNF-α) and various chemokines

  4. Innate immune response (vascular events, cellular events) V a s c u l a r events - local postcapillary venular endothelial cells: vascular vasodilation and exudation of fluid (due to IL-1, TNF-α, PGs, Hi, PAF)- mediators derived from plasma: the fluid exsudate contains a variety of mediators – the components of cascades: - the complement system (C5a and C3a –stimulate mast cells) - the coagulation system (thrombin, fibrin) - the fibrinolytic systém (plasmin) - the kinin system (bradykinin)

  5. - Innate immune response C e l l u l a r e v e n t s - expression of adhesion molecules on the cell surfaces mast cells, polymorphonuclear leucocytes, monocytes/ macrophages, vascular endothelial cells, platelets, natural killer cells (NKcells), neurons Mediators derived from cells: PGs, NO, histamine, cytokines…

  6. Adaptive immune response is more specific The key cells are the lymphocytes: . B cells – responsible for antibody production –the humoral immune response . T cells - important in the induction phase of the immune response - responsible for cell-mediated immune reaction T w o p h a s e s: Induction phase Effector phase

  7. - Adaptive immune response- • Induction phase • naive T cells bearing either the CD4 or CD8 coreceptors • are presented with antigen • - CD8-bearing cells proliferate further and develop into • cytotoxic T cells, which can kill virally infected cells • CD4-bearing Th cells are stimulated by cytokines • to develop into Th1 or Th2 cells • Th2 cells control mostlyantibody-mediated responses • ---they interact with B cells, which proliferate giving rise to • antibody-secreting plasma cells andmemory cells • Th1 cells proliferate, developing into cells that release • macrophage-activating cytokines. These cells, along with cytotoxic T cells control cell-mediated responses

  8. -Adaptive immune response- • Effector phase • involves antibody- and cell-mediated responses • Antibodies provide: • more effective ingestion of microorganisms • neutralisation of some viruses and of some bacterial toxins • Cell-mediated reactions involve: • - CD8 cytotoxic T cells interacting with and killing virus-infected cells • cytokine-releasing CD4 T cells: the cytokines enable macrophages to kill intracellular pathogens • memory cells - primed to react rapidly to the antigen that gave rise to that clone of cells next time an organism bearing that antigen is encountered

  9. Inappropriately deployed immune reactions = hypersensitivity reactions These underlie the autoimmune diseases, i.e. diseases caused by immune reactions directed at the host´s own tissues

  10. Immunosuppressant drugs

  11. - inhibit interleukin-2 production or action • ciclosporin, tacrolimus, sirolimus • inhibit cytokine gene expression • corticosteroids • inhibit purine and pyrimidine synthesis • azathioprine • block the T cell surface molecules involved in signalling • polyclonal and monoclonal antibodies • - act by cytotoxic mechanisms • cyclophosphamide, chlorambucil

  12. Usage in therapy: • autoimmune disease (some forms of haemolytic anaemia, glomerulonephritis…) • prevention /or therapy of • transplant rejection (kidneys, bone • marrow, heart, liver, etc.) • - combination - • Hazard: • decreased response to infections • facilitation of emergence of malignant • cells

  13. Ciclosporin • a fungal polypeptide with potent immunosuppresive activity • Pharmacokinetics • - i.v., oral absorption (rather poor-alternative formulations) • - hepatic metabolism-metabolites excreted in the bile • accumulation in most tissues at conc. 3 to 4 times that seen in the plasma • TDM?

  14. Unwanted reactions: • - nephrotoxicity • hepatotoxicity • hypertension

  15. Tacrolimus • - a macrolide antibiotic • i.v., orally • metabolized by the liver (drug-drug interactions) • TDM? • Unwanted reactions: • - neurotoxicity • - GIT upsets, metabolic disturbances (hyperglycaemia) reversible by reducing the dosage

  16. Glucocorticoids • restrain the clonal proliferation of Th cells through • decreasing transcription of the gene for IL-2 • - decrease the transcription of many other cytokine genes in both the induction and effector phases of the immune response

  17. Azathioprine is activated to 6-mercaptopurine (a pure analogue –antimetabolite - that inhibits DNA synthesis) by a cytotoxic action on dividing cells inhibits clonal proliferation in the induction phase of the immune response Unwanted reactions: - depression of the bone marrow, - nausea and vomiting

  18. PK/PD 6-MP in ALL of childhood Pharmacodynamics Pharmacokinetics 6-methyl MP TPMT first pass effect HPRT TGN (ERY) WBC 6-MP relaps AUC 1.5-3.5 x 109/l XO 6-thiouric acid

  19. Mycophenolate mofetil • A semisynthetic derivative of a fungal antibiotic • bioactivated to mycophenolic acid • Action (fairly selective): • restrains proliferation of both T and B lymphocytes • reduces the production of cytotoxic T cells • Kinetics: • Well absorbed from the GIT • Enterohepatic circulation-inactive glucuronides

  20. Monoclonal antibodies (mAbs) genetically engineered imunoglobulins that react with specific molecular target. They may be part mouse, part human (humanised or chimeric) or fully human. In chimeric mAbs, the antigen-recognising portion of a mouse antibody is joined to the framework of a human IgG molecule: Basiliximab - a chimeric mAb Daclizumab - a humanised mAb mAbs against the α-chain on the IL-2 receptor on Th cells the blockade of T cell signal transduction events - Used in acute rejection of kidney transplants

  21. Unwanted reactions: serious hypersensitivity reactions

  22. Current therapies based on manipulation of the immune response

  23. Immunoglobulins Normal human IgG derived from pooled human plasma can be used: - as a replacement therapy in antibody-deficiency states - to protect susceptible subjects against infections with hepatitis A virus, measles...

  24. Monoclonal antibodies • -infliximab • A chimeric mAb against the cytokine TNF-α used for rheumatoid arthritis and Crohn´s disease • abciximab • A chimeric mAb against the clotting receptor GpIIb/IIIa on platelets- used to prevent clotting in patients undergoing coronary angioplasty • -gentuzumab • A humanised mAb against an antigen on leukemia cells, used to treat relapsed acute myeloid leukemia • and others

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