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Anti-cytokine therapy

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Anti-cytokine therapy

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011 ZoltanBalajthy MolecularTherapies-Lecture 8 Anti-cytokinetherapy

  3. TÁMOP-4.1.2-08/1/A-2009-0011 Learning objectives of chapter 8. As the reason of many common diseases is the appearance of inflammatory process in our body (rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, insulin-dependent diabetes melitus, psoriasis, sepsis), the significance of anti-cytokine therapy is interpreted through the understanding both the processes and mechanisms of inflammation. Topicsinchapter 8 8.1. Development of septicshock and subsequentfailure of organ Migration of neutrophilfromvascularspace to tissues Effects of IL-1 , -β and TNF Stream Of cytolkines in sepsis 8.2. Development of inflammatoryresponse Synthesis of lipidmediators Iniciation of cytokinesynthesis of inflammation Synthesis of NO controlled by cytokine 8.3. Role of the Liver in Maintenance of Homeostasis Acutephaseresponse, acutephaseproteins (APP) 8.4. Time-Course of the Inflammatory Response During Sepsis Endothelial Activation, Coagulation and Fibrin Clot Formation 8.5. Collapse of Homeostasis 8.6. Anti-CytokineTherapy 8.7. Cancer therapy and monoclonal antibodies 8.8. How Can Immunity Be Applied for Treatment

  4. TÁMOP-4.1.2-08/1/A-2009-0011 Characterization of cytokines Cytokines are proteins of size ranging from 50 to 500amino-acids in average, and are major molecular messengersfor communication between cells. More than 200 cytokines have been identified and cloned. Cytokines share the following characteristics: they have very high affinity for their specific receptor; they act in a paracrine or autocrine fashion and are potent at picomolar to nano- molar concentrations. Today, cytokines have been classified into several classes based on structural or functional similarities: monokines, lymphokines, interleukins, colony stimulating factors, interferons, tumor necrosis factors and chemokines. Characteristic feature of cytokines: they take part of natural immunity, hematopoiesis, activation of lymphocyte, differentiation and initiation of inflammation. In many common diseases cytokine overproduction would happen giving the key targets for anti-cytokine treatments. Cytokine receptor family: hematopoietin, interferon, TNF, IL-1, TGF-β and chemokine receptors.

  5. 8.1. Developmentof SepticShock and SubsequentFailure of Organ Infection, Trauma, Burns Relase of Endotoxines or Ecosanoids, Complement Activation Inflammatory Cytokine Storm Small Mediator Molecules, vascular resistance ↓ Hypotension, Acidosis, Decreased Tissue Oxygenation Myocardial Suppression, Refractory Shock, Organ Ischemia Multiple Organ Failure, Disseminated Intravascular Coagulation, Death TÁMOP-4.1.2-08/1/A-2009-0011

  6. Migration of NeutrophilFromVascularSpacetoTissues circulating neutrophils systemic circulation TNF IL-1 ELAM NO IL-8 PG PAF ■■■ ■■■ ■■■ ■■■ ■■■ ■■■ ■■■ ■■■ endothelium smooth muscle extravascular space capillary leak neutrophil emigration into tissue ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● neutrophil degranulation and tissue damage ● ● ● ● ● ● ● TÁMOP-4.1.2-08/1/A-2009-0011

  7. StreamOf Cytolkinesin Sepsis HYPOTENSION TISSUE INJURY ORGAN FAILURE TNF DEATH IL-1 IL-6 C5a TÁMOP-4.1.2-08/1/A-2009-0011

  8. Results of IL-1  and β Fever Myalgias and JointPain Headach Loss of Appetite and Confusion MildHypertensionat LowConcentration of IL-1 HypotensionatIncreasedConcentration of IL-1 HemodynamicshockatHighConcentration of IL-1 IL-1α, IL-1β, and the (IL-1RA) (interleukin-1 receptor antagonist) play important rolein regulation of immune functions and inflammationprocess. Both IL-1α and IL-1β are pro-inflammatorycytokinesproduced by macrophages, monocytes, fibroblasts and dendritic cells TÁMOP-4.1.2-08/1/A-2009-0011

  9. Effect of Adrimistrationof TNF Core Body TemperatureIncreases NeutrophilCountDecreasingattheEarlyPhase WhiteBloodCells CountIncreasesintheLatePhase MeanArterialBloodPressureDecrease (Hypotensison) CoagulationParametersIncrease Mental Status Declines Myalgias / arthralgias TNF (Tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction. The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis. A TNF can bindto TNF-R inhomotrimerformthatcanactivate MAPK, NFκB orcelldeathsignaling. TÁMOP-4.1.2-08/1/A-2009-0011

  10. IL-1 and TNF Synergism Hypotension ans Schock Prostaglandin Production Cytotoxicity / Tumor necrosis Muscle proteolysis Lactic acidosis Anti-cytokines to Reduce Mortality in Sepsis Antibodies to TNF Soluble Receptors of TNF IL-1 receptor antagonist TÁMOP-4.1.2-08/1/A-2009-0011

  11. InflammatoryCytokines and Anti-Cytokines TÁMOP-4.1.2-08/1/A-2009-0011

  12. 8.2. Development of InflammatoryResponse Synthesisof LipidMediators phospholipids of plasma membrane PLA2, Phospholipases A2cleaves arachidonate lipoxygenases cyclooxigenase (COX -1) prostaglandin synthetase leukotrienes (LTA4 - LTE4) prostglandin H2 (PGH2) prostacyclin synthase thromboxane synthase other prostaglandins (PGD2, PGE2) prostacyclin (PGI2) thromboxanes (TXA2) Arachidonate is the major precursor of several classes of signal molecules: prostaglandins, prostacyclins, thromboxanes, and leukotrienes TÁMOP-4.1.2-08/1/A-2009-0011

  13. Development of InflammatoryResponse I. LPS - LPS binding protein complex (LBP) lipopolysaccharide (LPS) LPS binding protein (plasma) lysed bacterial cells LPS-LPB LPS-LPB CD14 TLR-4 NFκB pathway (TLR) LPS CD14, CD11/18, TLR-2/TLR-4 LPS Receptors lipoteichoic acid peptidoglycan - lipoteichoic acid neutrophil Inflammatory cytokines cytoplasm membrane monocyte TÁMOP-4.1.2-08/1/A-2009-0011

  14. Iniciation of CytokineSynthesisofInflammation Toll-like receptor p p IκB phosphorilation receptor activation  p65 p65 p65 p50 p50 p50  adaptor protein β IκB proteasomal degradation IκK complex nuclear translocation nukleus NFκB transcription transcription of inflammatorygenes (IL8, IL6, TNF) TÁMOP-4.1.2-08/1/A-2009-0011

  15. Blood stream cytokine receptor receptor L-arginine L-arginine iNO synthase iNO synthase nitric oxide nitric oxide NO activates soluble guanylate cyclase Endothelial cells NO activates soluble guanylate cyclase GTP cGMP GTP cGMP cGMP degreased cytoplasmic Ca2+ degreased cytoplasmic Ca2+ Smooth muscle cell Vasodilatation TÁMOP-4.1.2-08/1/A-2009-0011 Synthesis of NO controlledbycytokine

  16. 8.3. Roleof theLiverinMaintenanceofHomeostasis, (Inflammation) Cellsassociatedwithinitiatingtheacutphaseresponseareneutrophils monocytes and macrophages Released IL-1, TNF and IL-6 reachthecentralnervoussystem and theliver. Acutphaseproteinsproducedbylivercells: Complementproteins Coagulationproteins Proteinaseinhibtors Opsonins Serumamyloid A (SAA) C-reactive protein (CRP) TÁMOP-4.1.2-08/1/A-2009-0011

  17. Cytokines Prostaglandins Sickness behaviour Fever IL1β,IL6, TNF Blood vessel Cytokines, chemokines prostaglandines Lungs Infection Bone marrow Complement proteins Coagulation proteins Proteinase inhibtors Opsonins Acute phase response Blood vessel Monocytes, neutrophils Liver TÁMOP-4.1.2-08/1/A-2009-0011 AcutePhaseResponse

  18. TÁMOP-4.1.2-08/1/A-2009-0011 Inflammatorymediatorsthatmodulatehepatic APR synthesis TNF- IL-1 IL-6 LIVER ACUTE PHASE PROTEINS Complement proteins: C3, C5 and C1 inhibitor (6-8 X) Metal-binding proteins: Haptoglobulin, ceruloplasmin (1.5-2 x) Coagulation proteins: Fibrinogen (2-4 x) Von Willebrand factor Negative APRs: albumin, transferin (0.4-0.5 X) Major APRs: Serum amyolid A (100-1000 X) C-reactive protein Serum amyloid P component (SAP) Protein inhibitors: Plasminogen activator inhibitor I 2-antiplasmin

  19. 8.4. Time-Courseof theInflammatoryResponseDuring Sepsis TÁMOP-4.1.2-08/1/A-2009-0011

  20. EndothelialActivation, Coagulation and FibrinClot Formation I. Direct tissue injury Gram-negative bacteria lipopolysaccharide, endotoxin (LPS) Gram-pozitive bacteria CD 14 receptor Platelet-activating factor (PAF), arachidonic acid, leukotriens, Toll-like receptor lipoteichoic acid Activation of NFκB Pathway  Induction of proinflammatory cytokines inflammatory response LPS-LBP TNF IL-1 Plasminogen activator inhibitor VII a + tissue factor Microvascular coagulopathy tissue factor TÁMOP-4.1.2-08/1/A-2009-0011

  21. CoagulationResponse Pathways of Procoagulation Anticoagulation Pathway Fibrinolysis fibrin clot formation Fibrinogen Fibrin Profactors (V és VIII) activation Zimogenes (IX és XIII) activation Thrombin (IIa) Protrombin (II) Plasmin (+) Factor Xa + Factor Va PROTHROMBINASE Factor V Factor X + Plasminogen activated protein C TFPI Tissue Factor Pathway Inhibitor (+) Factor IXa + Factor VIIIa INTRINSIC TENÁZ Factor IX Factor VIII + (-) (-) PAI-1 (Plasminogen activator inhibitor 1) Plasminogen activators (-) VII a + Tissue Factor EXTRINSIC TENÁZ (X-ÁZ) (+) VII + Tissue Factor Aktivated pFrofactors Inactivation of (Va és VIIIa) TÁMOP-4.1.2-08/1/A-2009-0011

  22. EndothelialActivation, Coagulation and FibrinClot Formation II. endothelium Fibrinogen Fibrin Fibrin Clot organism Thrombin Prothrombin CD14 TLR-4 Activation of NFκB Pathway  Factor Xa + Factor Va Factor X inflammatory response Factor V Factor IX Factor IXa + Factor VIIIa LPS-LBP b c Factor VIII VII a + Induction of proinflammatory cytokines Tissue Factor Tissue Factor Inflammatory Responseto Infection Thrombotic Responseto Infection Fibrinolytic Responseto Infection TÁMOP-4.1.2-08/1/A-2009-0011

  23. Coagulation, FibrinClot Formation and Inhibition of Fibrinolysis endothelium fibrin clot formation Fibrinogen Fibrin organism Thrombin Protrombin CD14 TLR-4 TAF1 Activation of NFκB Pathway  fibrinolysis inhibition (thrombin activated fibrinolysis inhibitor) Factor Xa + Factor Va inflammatory response inflammatory response Factor V PAI-1 (plasminogen activator inhibitor 1) Factor IXa + Factor VIIIa LPS-LBP b c Factor VIII Induction of proinflammatory cytokines VII a + Tissue Factor Tissue Factor Inflammatory Responseto Infection Thrombotic Responseto Infection Fibrinolytic Responseto Infection TÁMOP-4.1.2-08/1/A-2009-0011

  24. Endogenous Activated Protein C Has MultipleMechanisms of Action organism endothelium fibrin clot formation Fibrinogen Fibrin CD14 TLR-4 Activation of NFκB Pathway  Thrombin Prothrombin TAF1 fibrinolysis inhibition (thrombin activated fibrinolysis inhibitor) Factor Xa + Factor Va inflammatory response inflammatory response Factor V PAI-1 (plasminogen activator inhibitor 1) activated protein C Factor IXa + Factor VIIIa b rolling c Factor VIII VII a + Protein C Catalyzed Inactivation Degreased Tissue Factor protein S protein C Tissue Factor LPS-LBP thrombospondin Inflammatory Responseto Infection Thrombotic Responseto Infection Fibrinolytic Responseto Infection TÁMOP-4.1.2-08/1/A-2009-0011

  25. NF-κB CD14 TLR-4 VCAM RAGE ICAM ICAM TNF- Neutrophil  adherence IL-1a LPS PAI-1 tPA IL-1b HMGB1 IL-6 Regulation of fibrinolysis TNF- monocytes macrophages Pro-inflammatory cytokines and chemokines MCP-1 MCP-1 TNF- IL-8 IL-8 TÁMOP-4.1.2-08/1/A-2009-0011 Contribution of high-mobility group box 1(HMGB1) tosepsis

  26. 8.5 Collapse of Homeostasis Proinflammatory mediators Tissue factor expression Thrombin production Endothelial injury Decreased Fibrinolysis Increased Coagulation Increased Inflammation Increased PAI-1 Increased TAF Reduced Protein C Homeostasis PAI : plasminogen activator inhibitor TAFI: thrombin activated fibrinolysis inhibitor TÁMOP-4.1.2-08/1/A-2009-0011

  27. Development of SepticShock and OrganFailure Septic Shock Sever Sepsis Infection Sepsis SIRS Mitochondrial Disfunction Organ Disfunction Microvascular Coagulation/ Thrombosis Multiple Organ Failer Death SIRS: systemic inflammatory response syndrome

  28. 8.6. Anti-CytokineTherapy antibodies (anti-IL-6R) Anticomplement Monoclonal Antibody Soluble Receptor (Enbrel) Receptor Antagonists (IL-1RA) IL-6 Antagonist Cytokines Antagonists (IL-10, IL-11, IL-13) TACE, ICE inhibittors Drotrecogin alfa TÁMOP-4.1.2-08/1/A-2009-0011 See: Anti-cytokinetherapeutics: history and update. Ratsimandresy RA, Rappaport J, Zagury JF. Curr. Pharm. Des. 2009;15(17):1998-2025. Review.

  29. TÁMOP-4.1.2-08/1/A-2009-0011 8.7 Cancer therapy and monoclonal antibodies Monoclonal antibodies have been seen as a breakthrough in cancer therapy. However, there are problems with their use. These include the targeting of the antibody to the tumor. There are few if any molecules that are cancer-cell- specific and many markers of cancer are merely up-regulated or mutated forms of natural cellular products. Additionally, cancers are heterogeneous with respect to antigen production and therefore an antibody may not recognize every cancer cell. Sadly, removal of all cancer cells is a prerequisite for a cure. One of the first tasks is therefore the recognition of a target molecule on the cancer. Herceptin in breast cancer therapy see: Cell Cycle and Cancer Therapy, p53

  30. TÁMOP-4.1.2-08/1/A-2009-0011 8.8. How Can Immunity Be Applied for Treatment? Immunity is a specific system dealing with defensive mechanism. It is useful for prevention, via destroying of foreign body that enters or invades into the human body before it can generate further problems. However, the present concept transform to the usage of immunity for medical treatment. The immunotherapy is a new highlight in immunology. There are many forms of immune-related treatments. A. Immunomodulation Therapy: Immunomodulation therapy is a new way of treatment making use of modification of immunity systern to help curative process of some diseases. This is widely used for several treatments. Immunosuppressants: inhibits immune response in organ transplantation and autoimmune diseases. The drugs are: - Calcineurin inhibitors (Specific T-cell inhibitors). Cyclosporine (Ciclosporin), - Antiproliferative drugs (Cytotoxic drugs). Azathioprine, Cyclophosphamide, Methotrexate, - Glucocorticoids. Prednisolone and others - Antibodies. Muromonab CD3, Antithymocyteglobin (ATG), Rho (D) immuneglobin, Efalizumab.

  31. Immunostimulants • Increase the immune response, useful in infections, immunodeficiency (for example, AIDS) and cancers. • Immunostimulant drugs: • They stimulate the immune system to fight against immunodeficiencies (like AIDS), infections and cancers. • Levamisole. An antihelmintic drug that also restores functions of B lymphocytes, • T lymphocytes, monocytes and macrophages. Hence it has been used in colon cancer • along with 5-FU. • - Thalidomide. Different effects of this old drug have been utilized in conditions such as: • Erythemanodosumleprosum: Anti-inflammatory effect • Multiple myleoma: Anti-angiogenesis • Rheumatoid arthritis: Anti TNF effect. • - BCG. Used in carcinoma bladder. • - Recombinant cytokines. • Interferons: In tumors and chronic hepatitis B and C • interleukin 2 (aldeslukin): has been used in renal cell carcinoma and melanoma

  32. B. Antibody Treatment : Antibody treatment is any treatment making use of administration of immunoglobulin or antibody. This is famous for a long time. Direct passive immunization is the good example. The most well-know situations are tetanus antitoxin injection and rabies immunoglobulin for preventive and therapeutic purposes. See chapter 6. C. Therapeutic Vaccination Indeed vaccine is used for prevention and described as an active immunization. However, the present role of vaccine changes to more usefulness in curative treatment process. Vaccination against human papillomavirus infection to prevent the development of tumors. D. Cytokine Treatment Cytokine treatment or cytokine therapy is another mode of immune - related treatment. Indeed, cytokine is a product in cellular process of cell-mediated immunity process. Cytokine treatment is used for medical treatment of many diseases especially for many viral infections. This is comparable to antibody treatment, which makes usefulness of humoral immunity for treatment. E. Gene Therapy Seechapter 4. and 10.

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