Anti-cytokine therapy

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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes 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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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. - PowerPoint PPT Presentation

Transcript of Anti-cytokine therapy

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

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ANTI-CYTOKINE THERAPY

Zoltan BalajthyMolecular Therapies- Lecture 8

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

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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.

Topics in chapter 8

8.1. Development of septic shock and subsequent failure of organMigration of neutrophil from vascular space to tissuesEffects of IL-1 , -β and TNF Stream Of cytolkines in sepsis

8.2. Development of inflammatory response Synthesis of lipid mediatorsIniciation of cytokine synthesis of inflammationSynthesis of NO controlled by cytokine

8.3. Role of the Liver in Maintenance of HomeostasisAcute phase response, acute phase proteins (APP)

8.4. Time-Course of the Inflammatory Response During SepsisEndothelial Activation, Coagulation and Fibrin Clot Formation

8.5. Collapse of Homeostasis

8.6. Anti-Cytokine Therapy

8.7. Cancer therapy and monoclonal antibodies

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8.8. How Can Immunity Be Applied for Treatment

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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- and chemokine receptors.β

Characterization of cytokines

Cytokines are proteins of size ranging from 50 to 500 amino-acids in average, and are major molecular messengers for communication between cells. More than 200 cytokineshave been identified and cloned.

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Infection, Trauma, BurnsRelase of Endotoxines orEcosanoids, 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

8.1. Development of Septic Shock and Subsequent Failure of OrganTÁMOP-4.1.2-08/1/A-2009-0011

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endothelium smooth muscle

systemic circulation

TNF IL-1

extravascular space

capillary leak

PAF PG NO ELAM IL-8■■■■■■■■■■■■■■■■■■■■■■■■

●●●●● ●●●

●●●●

●●●

●● ●●●●

●●● ●●

●●●●

●●●

neutrophil emigration into tissue

neutrophil degranulationand tissue damage

circulating neutrophils

Migration of Neutrophil From Vascular Space to TissuesTÁMOP-4.1.2-08/1/A-2009-0011

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HYPOTENSION

TISSUE INJURY

ORGAN FAILURE

DEATH

C5a

TNF

IL-1IL-6

Stream Of Cytolkines in SepsisTÁMOP-4.1.2-08/1/A-2009-0011

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Results of IL-1 and β

Fever

Myalgias and Joint Pain

Headach

Loss of Appetite and Confusion

Mild Hypertension at Low Concentration of IL-1

Hypotension at Increased Concentration of IL-1

Hemodynamic shock at High Concentration of IL-1

IL-1 , IL-1 , and the (IL-1RA)α β (interleukin-1 receptor antagonist) play important role in regulation of immune functions and inflammation process. Both IL-1 and IL-1 are α β pro-inflammatory cytokines produced by macrophages, monocytes, fibroblasts and dendritic cells

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Effect of Adrimistration of TNF

Core Body Temperature Increases

Neutrophil Count Decreasing at the Early Phase

White Blood Cells Count Increases in the Late Phase

Mean Arterial Blood Pressure Decrease (Hypotensison)

Coagulation Parameters Increase

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 bind to TNF-R in homotrimer form that can activate MAPK, NFκB or cell death signaling.

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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

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Inflammatory Cytokines and Anti-Cytokines

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phospholipids of plasma membrane

arachidonate

PLA2, Phospholipases A2 cleaves

leukotrienes(LTA4 - LTE4)

lipoxygenases

prostglandin H2(PGH2)

other prostaglandins(PGD2, PGE2)

prostacyclin(PGI2)

thromboxanes(TXA2)

cyclooxigenase (COX -1)

prostaglandin synthetase

prostacyclin synthase thromboxane synthase

Arachidonate is the major precursor of several classes of signal molecules: prostaglandins, prostacyclins, thromboxanes, and

leukotrienes

8.2. Development of Inflammatory ResponseSynthesis of Lipid Mediators

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lysed bacterialcells

LPS

LPS binding protein(plasma)

LPS - LPS binding proteincomplex (LBP)

TLR-4CD14

LPS-LPB

LPS-LPB

NFκBpathway

CD14, CD11/18, TLR-2/TLR-4LPS Receptors

Inflammatorycytokines

Development of Inflammatory Response I.

r r rr r r rrr

rrr

rrrr rrrr

lipoteichoicacid

peptidoglycan -lipoteichoic acid

cytoplasm membrane

(TLR)

lipopolysaccharide (LPS)

neutrophil

monocyte

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adaptorprotein

β p65 p50

IκB

IκB proteasomal degradation

p65 p50

p65 p50transcription

nukleus

IκK complex

phosphorilation p p

nuclear translocation

receptor activation

transcription of inflammatory genes (IL8, IL6, TNF)

Toll-like receptor

NFκB

Iniciation of Cytokine Synthesis of Inflammation

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cytokine

L-arginine

nitric oxide

NO activates soluble guanylate cyclase

GTPcGMP

degreased cytoplasmic Ca2+

receptor

Vasodilatation

Smooth musclecell

Endothelialcells

iNO synthaseL-arginine

nitric oxide

cGMP

receptor

iNO synthase

GTPcGMP

degreased cytoplasmic Ca2+

NO activates soluble guanylate cyclase

Blood stream

Synthesis of NO controlled by cytokine

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Cells associated with initiating the acut phase response are neutrophilsmonocytes and macrophages

Released IL-1, TNF and IL-6 reach the central nervous system and the liver.

Acut phase proteins produced by liver cells:

Complement proteinsCoagulation proteinsProteinase inhibtorsOpsonins

Serum amyloid A (SAA)C-reactive protein (CRP)

8.3. Role of the Liver in Maintenance of Homeostasis, (Inflammation)TÁMOP-4.1.2-08/1/A-2009-0011

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Blood vessel

Blood vessel

Bone marrow

Prostaglandins

Cytokines

Fever

Sickness behaviour

IL1β,IL6, TNF

Infection

Cytokines, chemokinesprostaglandines

Acute phaseresponse

Monocytes, neutrophils

Complement proteinsCoagulation proteinsProteinase inhibtors

Opsonins

Lungs

Liver

Acute Phase ResponseTÁMOP-4.1.2-08/1/A-2009-0011

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LIVER

TNF-IL-1IL-6

ACUTE PHASE PROTEINS

Complement proteins:C3, C5 and C1 inhibitor (6-8 X)

Coagulation proteins:Fibrinogen (2-4 x)Von Willebrand factor

Protein inhibitors:Plasminogen activator inhibitor I2-antiplasmin

Metal-binding proteins:Haptoglobulin, ceruloplasmin (1.5-2 x)

Negative APRs: albumin, transferin (0.4-0.5 X)

Major APRs:Serum amyolid A (100-1000 X)C-reactive proteinSerum amyloid P component (SAP)

Inflammatory mediators that modulate hepatic APR synthesis TÁMOP-4.1.2-08/1/A-2009-0011

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8.4. Time-Course of the Inflammatory Response During SepsisTÁMOP-4.1.2-08/1/A-2009-0011

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Induction of proinflammatory cytokines

tissue factor

TLR-4CD14

TLR-4

CD14

LPS-LPBLPS-LPB

LPS-LPBLPS-LPB

LPS-LBP

Activation of NFκB

Pathway

tissue factor

VII a+

TNFIL-1

Platelet-activating factor (PAF),arachidonic acid, leukotriens,

Plasminogen activator inhibitor

Directtissue injury

Microvascularcoagulopathy

Gram-negative bacteria

Gram-pozitive bacteria

CD 14receptor

Toll-like receptor

lipopolysaccharide, endotoxin (LPS)

lipoteichoicacid

inflammatory response

Endothelial Activation, Coagulation and Fibrin Clot Formation I.TÁMOP-4.1.2-08/1/A-2009-0011

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Factor IXa +

Factor VIIIa

INTRINSIC TENÁZ

Thrombin (IIa)Protrombin (II)

Fibrinogen Fibrinfibrin clot formation

VII a+

Tissue Factor

EXTRINSIC TENÁZ (X-ÁZ)

Factor Xa +

Factor Va

PROTHROMBINASE

Factor VIII +

Factor V

Factor IX

Factor X +

Profactors (V és VIII) activation

Zimogenes (IX és XIII) activation

Coagulation Response

(+)

(+)

VII +

Tissue Factor(+)

TFPITissue Factor

Pathway Inhibitor(-)

Fibrinolysis

Aktivated pFrofactors Inactivation of (Va és VIIIa)

PAI-1(Plasminogen activator

inhibitor 1)

Plasmin

Plasminogen

Plasminogenactivators

activatedprotein C

(-)

(-)

Pathways of Procoagulation Anticoagulation Pathway

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Endothelial Activation, Coagulation and Fibrin Clot Formation II.

b

Tissue Factor

c

Factor IXa +

Factor VIIIa

Thrombin

Factor IX

Prothrombin

Fibrinogen Fibrin Fibrin Clot

endothelium

TLR-4CD14

TLR-4

CD14

TLR-4

CD14TLR-4

CD14 LPS-LPB

LPS-LPB

LPS-LPBLPS-LPB

LPS-LPBLPS-LPB

LPS-LBP

CD14

TLR-4

Inflammatory Response

to Infection

Thrombotic Response

to Infection

Fibrinolytic Response

to Infection

organism

Tissue Factor

VII a+

Factor XFactor Xa

+Factor Va

Factor VIII

Factor V

Activation of NFκB

Pathway

inflammatory response

Induction of proinflammatory cytokines

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b

Tissue Factor

c

Factor IXa +

Factor VIIIa

ThrombinProtrombin

Fibrinogen Fibrin

endothelium

TLR-4CD14

TLR-4

CD14

TLR-4

CD14TLR-4

CD14 LPS-LPB

LPS-LPB

LPS-LPBLPS-LPB

LPS-LPBLPS-LPB

LPS-LBP

CD14

TLR-4

organism

Tissue Factor

VII a+

Factor Xa +

Factor Va

Factor VIII

Factor V

TAF1(thrombin activated fibrinolysis inhibitor)

PAI-1(plasminogen activator

inhibitor 1)

fibrinolysis

inhibition

TNFIL6, IL1TNF

IL6, IL1

inflammatory response

inflammatory response

Activation of NFκB

Pathway

Induction of proinflammatory cytokines

fibrin clot formation

Coagulation, Fibrin Clot Formation and Inhibition of Fibrinolysis

Inflammatory Response

to Infection

Thrombotic Response

to Infection

Fibrinolytic Response

to Infection

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b

Tissue Factor

c

Factor IXa +

Factor VIIIa

ThrombinProthrombin

Fibrinogen Fibrin

endothelium

TLR-4CD14

TLR-

4

CD14

TLR-4

CD14TLR-4

CD14 LPS-LPB

LPS-LPB

LPS-LPBLPS-LPB

LPS-LPBLPS-LPB

LPS-LBP

CD14

TLR-4

organism

Tissue Factor

VII a+

Factor Xa +

Factor Va

Factor VIII

Factor V

TAF1(thrombin activated fibrinolysis inhibitor)

PAI-1(plasminogen activator

inhibitor 1)

TNFIL6, IL1TNF

IL6, IL1

thrombospondin

protein Sprotein C

Protein C Catalyzed InactivationDegreased

rolling

activatedprotein C

Endogenous Activated Protein C Has Multiple Mechanisms of Action

Activation of NFκB

Pathway

inflammatory response

inflammatory response

Inflammatory Response

to Infection

Thrombotic Response

to Infection

Fibrinolytic Response

to Infection

fibrinolysis

inhibition

fibrin clot formation

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TLR-4CD14

TLR-

4

CD14

LPS-LPBLPS-LPB CD14

TLR-4

HMGB1

RAGE VCAM ICAM

NF-κB

PAI-1tPA

TNF-

MCP-1IL-8

MCP-1IL-8

ICAM

Neutrophil adherence

Regulation offibrinolysis

TNF-IL-1aIL-1bIL-6

Pro-inflammatorycytokines andchemokines

monocytesmacrophages

LPS

Contribution of high-mobility group box 1(HMGB1) to sepsis

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Increased Coagulation

Increased Inflammation

Decreased FibrinolysisProinflammatory mediatorsTissue factor expressionThrombin productionEndothelial injury

Increased PAI-1Increased TAFReduced Protein C

PAI : plasminogen activator inhibitorTAFI: thrombin activated fibrinolysis inhibitor

Homeostasis

8.5 Collapse of Homeostasis

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Infection SIRS SepsisSeverSepsis

SepticShock

Development of Septic Shock and Organ Failure

MitochondrialDisfunction

OrganDisfunction

Multiple Organ Failer

Death

MicrovascularCoagulation/Thrombosis

SIRS: systemic inflammatory response syndrome

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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

8.6. Anti-Cytokine Therapy

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See: Anti-cytokine therapeutics: history and update.Ratsimandresy RA, Rappaport J, Zagury JF.Curr. Pharm. Des. 2009;15(17):1998-2025. Review.

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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 theantibody 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

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8.8. How Can Immunity Be Applied for Treatment?

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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, Antithymocyte globin (ATG), Rho (D) immuneglobin, Efalizumab.

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ImmunostimulantsIncrease 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:Erythema nodosum leprosum: Anti-inflammatory effectMultiple myleoma: Anti-angiogenesisRheumatoid 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

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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 treatmentprocess. Vaccination against human papilloma virus 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 TherapySee chapter 4. and 10.